Showing papers on "Diazomethane published in 2012"

Iron-Catalyzed Cyclopropanation in 6 M KOH with in Situ Generation of Diazomethane

Abstract: Diazomethane is a common and versatile reagent in organic synthesis whose broader use is generally impeded by its explosiveness and toxicity. Here we report that a simple iron porphyrin complex catalyzes the cyclopropanation of styrenes, enynes, and dienes under the demanding conditions [aqueous 6 molar potassium hydroxide (KOH) solution, open to air] necessary for the in situ generation of diazomethane from a water-soluble diazald derivative. A biphasic reaction medium arising from the immiscibility of the olefin substrates with water appears essential to the overall efficiency of the process. The work we describe highlights an approach to catalysis with untoward reactive intermediates, in which the conditions for their generation under operationally safe regimes dictate catalyst selection.

Catalytic Trimerization of Bis-silylated Diazomethane

Abstract: (Me3Si)2CNN isomerizes upon addition of traces of [Me3Si]+ ions to give (Me3Si)2NNC, which then undergoes an unusual trimerization reaction to give exclusively 4-diazenyl-3-hydrazinylpyrazole. As catalyst the isonitrilium ion, [(Me3Si)2NNC(SiMe3)]+, was identified and fully characterized. Experiments and computations indicate a three-step reaction including isomerization of diazomethane, a C–C or N–C coupling, and a formal cycloaddition reaction. The kinetics and thermodynamics are discussed on the basis of DFT calculations.

One Pot, Two Phases: Iron‐Catalyzed Cyclopropanation with In Situ Generated Diazomethane

Abstract: Tamed! The safe handling of diazomethane can be accomplished by a two-phase reaction. After being generated in aqueous media, the highly reactive species transfers to the organic phase and directly converts alkenes into cyclopropanes (see scheme). An air-stable iron(III) porphyrin complex serves as the catalyst.

Rates of fatty acid oxidations by P450 compound I are pH dependent.

Abstract: Cytochrome P450 enzymes (CYPs or P450s) are ubiquitous heme-containing enzymes with protein thiolate from cysteine serving as the fifth ligand to iron.[1] Most P450s catalyze oxidation reactions, and hepatic P450s oxidize many xenobiotics as well as most of the drugs used by humans.[2] The active oxidants in P450s are widely thought to be oxoiron(IV) porphyrin radical cations analogous to the so-called Compound I transients formed by reactions of peroxidase and catalase enzymes with hydrogen peroxide.[3] P450 Compounds I have not been observed under turnover conditions, but they can be prepared by “shunt reactions” where resting P450s are oxidized by hydroperoxy species. Shunt reactions were implicated early in P450 studies,[4] and spectroscopic evidence that Compound I transients were formed in these reactions accumulated over the past two decades.[5] The best characterized P450 Compound I is that formed by reaction of CYP119 with m-chloroperoxybenzoic acid (MCPBA).[5b, 5d] Much research has focused on understanding P450-catalyzed hydroxylations,[6] but direct kinetic studies of P450 Compounds I are in their infancy. P450-catalyzed hydroxylations of fatty acids, often at unactivated C-H positions, have a special distinction in that the search for fatty acid hydroxylase enzymes drove research that led to the discovery of one of the first characterized P450 enzymes.[7] Recently, we reported that rate constants for fatty acid oxidations by CYP119 Compound I were dependent on glycol co-solvent concentrations.[8] We now report that both the rates and regioselectivities of fatty acid oxidations by CYP119 Compound I are highly dependent on pH, further implicating a rate-determining conformational changes in the complex of Compound I with substrate for long chain fatty acids. Kinetic studies of dodecanoic (lauric) acid oxidations by CYP119 Compound I purportedly under the same reaction conditions gave different rate constants. Rittle and Green found that the reaction was so fast that only an apparent second-order rate constant could be obtained,[5d] whereas we found that saturation kinetics could be observed leading to a distinct binding constant and first-order rate constant.[8] Given the obvious environment effect we recently observed and the evidence that the rate-determining step involved a conformational change, we explored the possibility that pH effects influenced the kinetics of fatty acid oxidations. The kinetics of reactions of octanoic (caprylic) acid, dodecanoic (lauric) acid, and hexadecanoic (palmitic) acid with CYP119 Compound I were studied at varying pH using the stopped-flow kinetic method employed previously.[5d, 8] In a four-syringe stopped-flow kinetic unit, Compound I was produced by oxidation of the ferric enzyme with MCPBA, aged for 100 ms, and mixed with substrate. The rate of formation of ferric enzyme as Compound I reacted was followed. Details of the method have been reported[8–9] and are summarized in the Supporting Information. Results are in Table 1. When pH < 7.4, we observed curvature in the kinetic plots indicating saturation kinetics with reversible formation of a complex and rate-limiting first-order reaction of the complex. At pH 7.4, the rates increased so rapidly with concentration that we were not able to observe curvature in the plots. Table 1 Rate constants for reactions of fatty acids with CYP119 Compound I.[a] Perdeuterated acids were studied for comparison to several of the results with non-deuterated acids, and the kinetic isotope effects (KIEs) in the first-order rate constants are listed in Table 1. Perdeuterated octanoic acid reacted less rapidly than the non-deuterated isotopomer giving modest KIEs. For dodecanoic acid and hexadecanoic acid, the perdeuterated isotopomers reacted with the same rate constants as the non-deuterated substrates. The saturation kinetics data requires that a complex of enzyme and substrate is formed reversibly, but the small or absent KIEs indicate that the first-formed complex is non-reactive and must isomerize to a reactive form (see Supporting Information). Such a model for reactions of CYP119 Compound I was presented previously.[5d, 8] Because the KIEs for dodecanoic acid and hexadecanoic acid are 1.0 at all pH, the oxidation rate constants for the deuterated acids are greater than the rate-limiting isomerization rate constant. Using a KIE of kH/kD ≈ 7 as found for intramolecular KIEs for dodecanoic and hexadecanoic acids,[8] the oxidation rate constant for hexadecanoic acid at pH 7.3 would be greater than 3500 s−1. Further assuming zero entropy of activation for the first-order process, the activation energy for the reaction at 4 °C would be less than 12 kcal/mol, a remarkably low activation energy for functionalization of unactivated C-H bonds. For comparison, Bell and Groves recently reported a highly reactive model for P450 Compound I,[10] and extrapolation of their Bronsted-Evans-Polanyi relationship predicts that their model would react with an unactivated C-H bond at 10 °C with a rate constant of 0.01 M−1 s−1 or activation energy of about 15 kcal/mol. The pH effect on the kinetics found here explains diverse results previously reported for reactions of dodecanoic acid with CYP119 Compound I. Rittle and Green found that reaction of dodecanoic acid in 100 mM phosphate buffer at 4 °C was too fast to observe saturation kinetics and reported an apparent second-order rate constant of kapp = 1.2 × 107 M−1 s−1 at a reported pH 7.[5d] We found that the reaction at pH 7.0 displayed saturation kinetics, but the reaction at pH 7.4 studied here has exactly the same rate constant as found by Rittle and Green. In a similar manner, the apparent rate constant for reaction of octanoic acid previously reported was kapp = 4.5 × 105 M−1 s−1 at pH 7,[5d] and we found a similar rate constant at pH 7.4. Thus, careful measurement of pH is necessary in P450 Compound I kinetic studies. The results clearly demonstrate that the isomerization reactions are strongly accelerated in increasingly basic solutions. Plots of log kexp versus pH demonstrate good linearity (Figure 2), and the slopes, which give the order of dependence on hydroxide concentration, are 3.3 ± 0.1 (octanoic acid), 3.4 ± 0.7 (dodecanoic acid), and 3.5 ± 0.1 (hexadecanoic acid). These values indicate a minimum of two competing reactions in the rate-determining step, one third-order in hydroxide, and the other fourth-order in hydroxide (see Supporting Information). Based on the pH range of the kinetic effect, the rate-determining isomerization reactions appear to involve fast reactions for deprotonated forms of histidine residues. CYP119 contains seven histidines, three of which are within 11 A of the heme iron in a reported structure,[11] but identification of histidines controlling the rates of the isomerization reactions would seem to require studies with site-directed mutants. Figure 2 Plots of log kexp versus pH. The lines are linear regression fits. The regioselectivities of the oxidation reactions also were found to be dependent on the pH and demonstrate competing reactions with different kinetic order in hydroxide (Table 2). In these experiments, the hydroxylation product mixture was treated with diazomethane to give methyl ester products that were analyzed by GC for quantification and GC-mass spectrometry for identification.[12] An example of the pH effect on regioselectivity is shown in Figure 3 for dodecanoic acid reactions at pH 7.0 and 7.4 Figure 3 GC traces of methyl esters of products from oxidation of dodecanoic acid at pH 7.0 (A) and pH 7.4 (B). The products elute as follows: methyl 9-hydroxydodecanoate (23.4 min), methyl 10-hydroxydodecanoate (24.1 min), methyl 11-hydroxydodecanoate (25.2 min). ... Table 2 Regioselectivity of oxidations of fatty acids by CYP119 Compound I.[a] The regioselectivities for oxidations of dodecanoic acid and hexadecanoic acid at pH 7.0 and 7.4 are listed in Table 2. At the lower pH, dodecanoic acid was oxidized at the ω-1, ω-2, and ω-3 positions in comparable amounts, but, at higher pH, it was oxidized almost exclusively at the ω-1 and ω-2 positions. Previously, dodecanoic acid oxidation by CYP119 under turnover conditions was reported to give mainly the ω-1 and ω-2 products in an approximate 3:1 ratio,[12a] and reactions of CYP119 Compound I were reported to give comparable amounts of ω-2 and ω-1 alcohols[5d] or comparable amounts of the three alcohol products found here.[8] The regioselectivity of oxidation of hexadecanoic acid behaved much like that of dodcanoic acid; at pH 7.0, the ω-1, ω-2, and ω-3 products were formed in an approximate 1:2:1 ratio, and at higher pH, the ω-3 product decreased considerably. In conclusion, we have found that the rates of reactions with CYP119 Compound I with fatty acids are highly dependent on the pH of the medium with rates increasing with greater than third order in base concentration as the pH is raised. The rate-determining steps in the reactions are conformational changes in the complex of activated Compound I plus substrate that, one assumes, bring the substrate into intimate contact with the activated oxygen atom of the oxo-iron(IV) moiety, and the rates of those changes appear to be related to the protonation states of histidines. Combined with the previous demonstration that glycol co-solvents strongly affect rates of fatty acid oxidations by CYP119 Compound I,[8] a high mechanistic complexity for the hydroxylation reactions is apparent. One should exercise caution in predictions of rates of C-H hydroxylations by P450 Compounds I until more detailed information is available.

Synthesis and Antimicrobial Activity of Amido Linked Pyrrolyl and Pyrazolyl-Oxazoles, Thiazoles and Imidazoles.

Abstract: The title compounds (V), (VII) and (VIII) are obtained by 1,3-dipolar cycloaddition of TosMic or diazomethane to the respective cinnamamide derivatives (III).

Synthesis, reactions, and rearrangements of 2,4-diazabicyclo〔3.1.0〕hexan-3-ones

Abstract: Copper-mediated cyclopropanation of dihydroimidazolones (I) using diazomethane (II) and methyl diazoacetate (VI) provides access to diazabicyclohexanones (IIIa), (IIIb), (VII), and (XI) and the first diaza[4.3.1]propellane (IIIc).

N‐Alkylation of N‐Arylsulfonyl‐α‐amino Acid Methyl Esters by Trialkyloxonium Tetrafluoroborates.

Abstract: In this work we present the results obtained for the N-alkylation of a series of N -arylsulfonyl-α-amino acid methyl esters bearing different substituents at the 4-position of the sulfonamide aromatic ring. In particular, we compare the reactivity of these species with diazomethane and trimethyloxonium tetrafluoroborate in N-methylation processes. Diazomethylation is unsuccessful for N -arylsulfonamide derivatives containing electron-releasing groups on the aromatic ring. In these cases trimethyloxonium tetrafluoroborate is the reagent of choice for the direct and quantitative N-methylation. Further we extend our evaluation to the use of triethyloxonium tetrafluoroborate. This reagent shows to be very efficient in order to prepare N -ethyl derivatives of N -arylsulfonyl-α-amino acid methyl esters. An experimental protocol similar to that used for N-methylation with trimethyloxonium tetrafluoroborate is applied for the N-ethylation.

Synthesis and fungitoxicity of 1-[N-benzoyl]-3-(21-substituted-31-sulphonyl-51-methoxyindol-31-yl)-2-pyrazolines and 1-(N-phenylsulphonyl)-3-(21-substituted-31-sulphonyl)-(51-methoxyindol-31-yl)-2-pyrazolines.

Abstract: Starting material 2-substituted-3-vinylsulphonyl-5-methoxyindols (1a-g) have been synthesized from easily available 2-substituted-5-methoxyindols in 1, 4-dioxane and chlorosulphonyl chloride. Compound (1a-g) reacts with triethyl amine in dry tetrahydrofuran and treated with diazomethane to form 3-(21-substituted-3-sulphonyl-51-methoxyindol-31-yl)-2- pyrazolines (2a-g). Compound (2a-g) reacts with benzoyl choride, potassium hydroxide and methanol to give 1-[N-Benzoyl- 3-(21-substituted-31-sulphonyl-51-methoxyindol-31-yld-2-pyrazolines (3a-g) and again reacts with benzenesulphonyl chloride in pyridine and neutralize with dilute HCl to formed 1-(N-phenylsulphonyl)-3-(21-substituted-31-sulphonyl)-51-methoxyindl- 31-yl)-2-pyrozalines (4a-g). Antifungal activity has been compaired with dithane M-45, a commercial fungicide, for their fungitoxic action against Phytophthora infestance and Collectotricum fulcatium, and the result correlated with their structural features.

Method for preparing pyrazol derivatives by utilizing gas diazomethane

Abstract: The invention relates to a method for preparing pyrazol derivatives by utilizing gas diazomethane. In the method, alkyne derivatives which are commercialized in the market or are easy to prepare are used as initial raw materials; at low temperature, the initial raw materials directly react with diazomethane gas which is continuously prepared from N-methyl-N-nitroso-p-tolutenesulfonamide under the alkaline condition so as to prepare the high-purity pyrazol derivatives, wherein R1 and R2 are C1-C4 linear chain, cycloalkyl group, -H or -COOR1/-COOR2, and benzene ring -OR1/-OR2 free of unsaturated functional group and carbonyl group. The method disclosed by the invention has the advantages that used raw materials are available, process condition is stable, operation is simple, and reaction yield and product purity are high; and the method is suitable for large-scale production, and a new thought and a new method are provided for simply and rapidly preparing pyrazol compounds.

Expedient Preparation of Trifluoromethyl-Substituted Benzofuranols.

Abstract: Direct access to 3-trifluoromethyl-substituted benzofuranols is presented. The products are obtained in good yields from commercially available salicylaldehydes by using in situ generated trifluoromethyl diazomethane and boron trifluoride as an activator. As shown in a representative example, the products can be transformed into the corresponding trifluoromethyl-substituted benzofurans.

Synthesis of N-benzyl oxylcarbonyl-3-amino-1-chlorine-4-benzene sulfenyl-2-butanol

Abstract: The invention relates to a method for synthesizing (2S. 3R)-N-benzoyloxycarbonyl-3-amino-1-chlorin-4-thiophenyl-2-butanol, which is prepared by nitridation, selective reduction and hydrolysis with N-benzoyloxycarbonyl-S-phenyl-L-cysteine as an initial raw material. The method comprises the following technical steps: adding pyridine and an acid activating agent into organic solvent I containing N-benzoyloxycarbonyl-S-phenyl-L-cysteine to react, and adding ether solution of diazomethane to react to obtain an intermediate compound I; dripping chlorine hydride ethyl acetate into organic solvent II of the intermediate compound I for heat preserving reaction for 1 to 2 hours at -20 to -40 DEG C to obtain a crude product of a compound II; pouring the crude product of the compound II into organicsolvent III containing a catalyst for reaction, and using inorganic acid to acidify the reaction product until the pH value is 2 to 4 to obtain N-benzoyloxycarbonyl-3-amino-1-chlorin-4-thiophenyl-2-butanol. The method has the advantages of high reaction safety, relatively high product yield, high product purity, good optical rotation of melting point and low cost.

A New Derivative of Galanthamine: Methylene Insertion into the Aromatic Ring in Place of Cyclopropanation.

Abstract: In the course of the reaction between galanthamine (I) and diazomethane, methylene insertion into the aromatic ring is observed instead of the expected cyclopropanation of the C—C double bond.

Synthesis of Trifluoromethyl‐Substituted Cyclopropanes via Sequential Kharasch—Dehalogenation Reactions.

Abstract: A two-step process for the synthesis of trifluoromethyl-substituted cyclopropanes is described. Halothane, an anesthetic agent, is added to olefins in a ruthenium-catalyzed Kharasch reaction. The resulting 1,3-dihalides are converted into cyclopropanes by dehalogenation with magnesium. This procedure represents an alternative to metal-catalyzed cyclopropanations involving trifluoromethyl diazomethane.

Synthesis of 3‐Pyrazolinyl Chlorins Related to Chlorophyll by 1,3‐Dipolar Cycloaddition Reaction from Methyl Pheophorbide‐a

Abstract: The synthesis of a series of 3-pyrazolinyl-substituted chlorins, possessing different basic skeletons of chlorophyll degradation products such as pheophorbide-a, pyropheophorbide-a, purpurin-18, purpurin-7, purpurin-5, chlorin-p 6, and chlorin-e 6, was fulfilled from methyl pheophorbide-a by chemical modification and 1,3-dipolar cycloaddition with diazomethane. The structures of new chlorins were characterized by ultraviolet (UV), infrared (IR), 1H NMR, and mass spectra and elemental analysis.

Synthetic method of diazomethane compound

Abstract: The invention provides a synthetic method of a diazomethane compound. Diazotized sulfonyl-3,5,5-trimethyl-2-cyclohexenyl acetate is decarboxylated under the action of neutral alumina to obtain the high-purity and high-yield diazomethane compound. The synthetic method is carried out without using nitrosyl chloride which has the characteristics of high toxicity and easy blasting as a reaction raw material is environmentally-friendly and safe. The reaction yield is good, all the reactions are carried out with the temperature in a range from 0 to room temperature, and requirements on energy are low. The posttreatment process of the final product is simple, so expensive silica gel column chromatography separation is avoided. The reactant alumina has the effects of impurity separation and product purification, so the high-purity sulfonyl diazomethane derivative can be obtained through simple reduced pressure pumping filtration and concentration.

Synthesis of Chalcones Derived from (+)‐ and (‐)‐Usnic Acids.

Abstract: A number of chalcones with the (+)- and (−)-usnic acid moieties were synthesized by the following sequence: the reaction of these acids with phenylhydrazine, reduction of the C(1)=O group with sodium borohydride, O-methylation of the intermediate compounds with diazomethane, and subsequent condensation with substituted benzaldehydes at the acetyl group.

Synthesis of Some New 3,4‐Disubstituted Pyrroles and Pyrazoles from (E)‐1‐(Arylsulfonylethylsulfonyl)‐2‐arylethene.

Abstract: The sulfonyl activated (E)-olefin (I) is used as synthon for novel pyrrole and pyrazole derivatives by 1,3-dipolar cycloaddition of tosylmethyl isocyanide (II) and diazomethane (IV), respectively