Cyclopropanation-ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin.

We present a short and efficient way of synthesizing two synthetically versatile 4-quinolone-3-carboxylate building blocks by cyclopropanation-ring expansion of 3-chloroindoles with α-halodiazoacetates as the key step. This novel transformation was applied towards the synthesis of the antibiotic drug norfloxacin.

Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives.

A new efficient total synthesis of the phenazine 5,10-dioxide natural products iodinin and myxin and new compounds derived from them was achieved in few steps, a key-step being 1,6-dihydroxyphenazine di-N-oxidation. Analogues prepared from iodinin, including myxin and 2-ethoxy-2-oxoethoxy derivatives, had fully retained cytotoxic effect against human cancer cells (MOLM-13 leukemia) at atmospheric and low oxygen level. Moreover, iodinin was for the first time shown to be hypoxia selective. The structure-activity relationship for leukemia cell death induction revealed that the level of N-oxide functionality was essential for cytotoxicity. It also revealed that only one of the two phenolic functions is required for activity, allowing the other one to be modified without loss of potency.

On the cause of low thermal stability of ethyl halodiazoacetates.

Rates for the thermal decomposition of ethyl halodiazoacetates (halo = Cl, Br, I) have been obtained, and reported herein are their half-lives. The experimental results are supported by DFT calculations, and we provide a possible explanation for the reduced thermal stability of ethyl halodiazoacetates compared to ethyl diazoacetate and for the relative decomposition rates between the chloro, bromo and iodo analogs. We have also briefly studied the thermal, non-catalytic cyclopropanation of styrenes and compared the results to the analogous Rh(II)-catalyzed reactions.

Synthesis of quinoline-3-carboxylates by a Rh(II)-catalyzed cyclopropanation-ring expansion reaction of indoles with halodiazoacetates.

In this letter, we report a novel synthesis of ethyl quinoline-3-carboxylates from reactions between a series of indoles and halodiazoacetates. The formation of the quinoline structure is probably the result of a cyclopropanation at the 2- and 3-positions of the indole followed by ring-opening of the cyclopropane and elimination of H-X.

Microporous Molecular Materials from Dipeptides Containing Non-proteinogenic Residues.

Dipeptides with two hydrophobic side chains have proved to be an exceptional source of microporous organic materials, but since previous structures were limited to the incorporation of only proteinogenic residues, their full potential as adsorbents has remained unexplored. Single-crystal XRD data for ten new compounds with non-proteinogenic L-2-aminobutanoic acid and/or L-2-amino-pentanoic acid are presented. The gas-phase accessibility of their crystal pores, with cross-sections of 2.3 to 5.1 Å, was monitored by CO2 and CH4 adsorption isotherms. Included CO2 was also detected spectroscopically by 2D MAS NMR. An extensive conformational analysis reveals that the use of linear rather than branched side chains (such as L-valine and L-isoleucine) affords peptides with a greater degree of conformational freedom and yields more-flexible channel surfaces that may easily adapt to a series of potential guest molecules.

1,4-Bis(2-diazo-acet-yl)piperazine.

The asymmetric unit of the title compound, C8H10N6O2, contains one-half mol-ecule, which is completed by a crystallographic center of symmetry. The piperazine ring adopts a chair conformation. In the crystal, weak C-H⋯O inter-actions link the mol-ecules into layers parallel to the bc plane. The crystal packing also exhibits short N⋯N contacts of 3.0467 (16) Šbetween the terminal diazo N atoms from neighbouring mol-ecules.

α-Bromodiazoacetamides - a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C-H insertion reactions.

In this work, we introduce a new class of halodiazocarbonyl compounds, α-halodiazoacetamides, which through a metal-free, ambient-temperature thermolysis perform intramolecular C-H insertions to produce α-halo-ß-lactams. When carried out with α-bromodiazoacetamides bearing cyclic side chains, the thermolysis reaction affords bicyclic α-halo-ß-lactams, in some cases in excellent yields, depending on the ring size and substitution pattern of the cyclic amide side chains.

A solid-state oxidation of 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfinate to 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfonate.

The organic acid-base complex 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfonate, C5H14N3(+)·C7H7O3S(-), was obtained from the corresponding 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfinate complex, C5H14N3(+)·C7H7O2S(-), by solid-state oxidation in air. Comparison of the two crystal structures reveals similar packing arrangements in the monoclinic space group P2(1)/c, with centrosymmetric 2:2 tetramers being connected by four strong N-H···O=S hydrogen bonds between the imine N atoms of two 1,1,3,3-tetramethylguanidinium bases and the O atoms of two acid molecules.

Nucleophilic halogenations of diazo compounds, a complementary principle for the synthesis of halodiazo compounds: experimental and theoretical studies.

Three new protocols for the nucleophilic halogenations of diazoesters, diazophosphonates, and diazopiperidinylamides as complementary methods to our previously reported electrophilic halogenations are presented for the first time. On the basis of hypervalent α-aryliodonio diazo triflate salts 1A, 2A, and 3A, the corresponding halodiazo compounds are generated via nucleophilic halogenations with tetrabutylammonium halides or potassium halides. The products from subsequent catalytic intermolecular cyclopropanations of the halodiazoesters and halodiazophosphonates and thermal intramolecular C-H insertion of the brominated diazopiperidinylamide are obtained in moderate to good yields after two steps. DFT calculations are presented for the diazoesters to give insight into the mechanism and transition states of the nucleophilic substitutions with the neutral nucleophiles dimethyl sulfide and triethylamine and the bromination with Br(-).

Combined bead polymerization and Cinchona organocatalyst immobilization by thiol-ene addition.

In this work, we report an unusually concise immobilization of Cinchona organocatalysts using thiol-ene chemistry, in which catalyst immobilization and bead polymerization is combined in a single step. A solution of azo initiator, polyfunctional thiol, polyfunctional alkene and an unmodified Cinchona-derived organocatalyst in a solvent is suspended in water and copolymerized on heating by thiol-ene additions. The resultant spherical and gel-type polymer beads have been evaluated as organocatalysts in catalytic asymmetric transformations.

Halodiazophosphonates, a new class of diazo compounds for the diastereoselective intermolecular Rh(II) catalyzed cyclopropanation.

(Halodiazomethyl)phosphonates 2A-C have been generated by a one-pot procedure via a clean, efficient, and rapid deprotonation/electrophilic halogenation sequence from diethyl diazomethylphosphonate 1 (EDP). Subsequent intermolecular Rh(II)-catalyzed cyclopropanation afforded the corresponding halocyclopropylphosphonates 3-10 in moderate to high yields and high diastereomeric ratios. Catalyst loadings down to 0.1 mol % as well as clean and selective product formation were achieved.

1,1'-(4,4'-Bipiperidine-1,1'-di-yl)bis-(2,2,2-trifluoro-ethanone).

The title compound, C(14)H(18)F(6)N(2)O(2), has a central center of symmetry with both piperidine rings occurring in regular chair conformations. Even though the structure is fairly compact with no sizable voids, the shortest H⋯O distance is as long as 2.58 Å.

2-Diazo-1-(1,1-dioxothio-morpholin-4-yl)ethanone.

In the mol-ecule of the title compound, C(6)H(9)N(3)O(3)S, at 105 K, the six-membered ring is predominantly found in the chair conformation, with 1.89 (14)% in the boat conformation. In the crystal structure, there are five inter-molecular C-H⋯O=C and C-H⋯O=S contacts less than 2.6 Å, as well as a weak C-H⋯N=N inter-action to the diazo group.

Identification of a new series of non-peptidic NK3 receptor antagonists.

The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK(3) receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK(3) receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils.

Computational study of cyclopropanation reactions with halodiazoacetates.

The mechanism of rhodium(II)-catalyzed cyclopropanation reactions with ethyl bromo-, chloro-, and iododiazoacetate has been studied with density functional theory calculations. The halodiazoacetates were shown to be remarkably kinetically active compared to ethyl diazoacetate, as demonstrated experimentally in a study of reaction rates and supported by the calculated low potential energy barriers for the rate-determining loss of dinitrogen. In the rhodium carbenoids formed from the halodiazoacetates, pi-interactions between the halogen, the carbenoid carbon, and one rhodium atom were found. These interactions provide an explanation for the relatively high stability of these carbenoids and, consequently, the existence of small but significant potential energy barriers for the cyclopropanation step. The predicted diastereomeric ratios correspond well with the experimental results. In addition to transition states in which the alkene approaches the carbenoid in an end-on manner, as described in computational studies of cyclopropanations with other diazo compounds, side-on trajectory transition states were found to be of importance. The relative energies of the side-on trajectory transition states compared to the end-on trajectory transition states were shown to be affected by both the substrate alkene and the carbenoid substituents, a fact that should be taken into consideration when using models to explain and predict the stereochemical outcome of cyclopropanation reactions.

A general approach for preparation of polymer-supported chiral organocatalysts via acrylic copolymerization.

Polymer-supported chiral organocatalysts, as well as most other forms of immobilized catalysts, are traditionally prepared by a postmodification approach where modified catalyst precursors are anchored onto prefabricated polymer beads. Herein, we report an alternative and more scalable approach where polymer-supported chiral enamine and iminium organocatalysts are prepared in a bottom-up fashion where methacrylic functional monomers are prepared in an entirely nonchromatographic manner and subsequently copolymerized with suitable comonomers to give cross-linked polymer beads. All syntheses have been conducted on multigram scale for all intermediates and finished polymer products, and the catalysts have proven successful in reactions taking place in solvents spanning a wide range of solvent polarity. While polymer-supported proline and prolineamides generally demonstrated excellent results and recycling robustness in asymmetric aldol reactions of ketones and benzaldehydes, the simplest type of Jørgensen/Hayashi diarylprolinol TMS-ether showed excellent selectivity, but rather sluggish reactivity in the Enders-type asymmetric cascade. The polymer-supported version of the first-generation MacMillan imidazolidinone had a pattern of reactivity very similar to that of the monomeric catalyst, but is too unstable to allow recycling.

tert-Butyl 4-(2-diazo-acet-yl)piperazine-1-carboxyl-ate.

The title crystal structure, C(11)H(18)N(4)O(3), is the first diazo-acetamide in which the diazo-acetyl group is attached to an N atom. The piperazine ring is in a chair form and hence the mol-ecule has an extended conformation. Both ring N atoms are bonded in an essentially planar configuration with the sum of the C-N-C angles being 359.8 (2) and 357.7 (2)°. In the crystal structure, the O atom of the diazo-acetyl group accepts two H atoms from C-H donors, thus generating chains of weak hydrogen-bonded R(2) (1)(7) rings.

Synthesis of acrylic polymer beads for solid-supported proline-derived organocatalysts.

A completely non-chromatographic and highly large-scale adaptable synthesis of acrylic polymer beads containing proline and prolineamides has been developed. Novel monomeric proline (meth)acrylates are prepared from hydroxyproline in only one step. Free-radical copolymerization then gives solid-supported proline organocatalysts directly in as little as two steps overall, without using any prefabricated solid supports, by using either droplet or dispersion polymerization. These affordable acrylic beads have highly favorable and adjustable swelling characteristics and are excellent reusable catalysts for organocatalytic reactions.

(1S,5R)-1-(4-Fluoro-phen-yl)-3-azonia-bicyclo-[3.1.0]hexane chloride.

The absolute structure of the title compound, C(11)H(13)FN(+)·Cl(-), has been determined. The five-membered ring has an envelope conformation with the N atom at the flap position. In the crystal structure, the Cl(-) anion links with the organic cation via N-H⋯Cl hydrogen bonding.

(1S,5R)-1-(3,4-Dichloro-phen-yl)-3-oxa-bicyclo-[3.1.0]hexan-2-one.

The absolute structure has been determined by X-ray analysis for the title compound, C(11)H(8)Cl(2)O(2). The five-membered ring of the mol-ecule is best described as a flattened envelope conformation with the methyl-ene C atom located 0.208 (2) Šbelow the plane formed by the other four atoms. A weak intermolecular C-H⋯O hydrogen bond is present in the crystal structure.