Cross metathesis of unsaturated epoxides for the synthesis of polyfunctional building blocks

The cross metathesis of 1,2-epoxy-5-hexene (1) with methyl acrylate and acrylonitrile was investigated as an entry to the synthesis of polyfunctional compounds. The resulting cross metathesis products were hydrogenated in a tandem fashion employing the residual ruthenium from the metathesis step as the hydrogenation catalyst. Interestingly, the epoxide ring remained unreactive toward this hydrogenation method. The saturated compound resulting from the cross metathesis of 1 with methyl acrylate was transformed by means of nucleophilic ring-opening of the epoxide to furnish a diol, an alkoxy alcohol and an amino alcohol in high yields.

Linking Solubility and Permeability Assays for Maximum Throughput and Reproducibility

Solubility and permeability are intimately linked in drug absorption processes. They have, however, been traditionally assayed separately. To support this linkage, a combined solubility/permeability assay was developed for determining absorption properties of chemical entities. First, solubility is determined at 4 pH values by comparing the concentration of a saturated compound solution to its dilute, known concentration. The filtered, saturated solution from the solubility assay is then used as input material for the membrane permeability determination. The permeability assay is a parallel artificial membrane technique whereby a membrane is created on a solid support parallel artificial membrane permeation assay (PAMPA). The 2 artificial membranes presented here model the gastrointestinal tract and the blood-brain barrier (BBB). Data are presented for control compounds, which are well documented in the literature and exemplify a range of solubility and membrane permeability. The advantages of the combination method are 1) reduction of sample usage and preparation time, 2) elimination of interference from compound precipitation in membrane permeability determination, 3) maximization of input concentration to permeability assay for improved reproducibility, and 4) optimization of sample tracking by streamlining data entry and calculations. BBB permeability ranking of compounds correlates well with literature CNS activity.

Carbon protonation of some phenylynamines in concentrated aqueous perchloric acid solution. Lowering of the upper limit for the pKa of phenylynammonium ions

Rates of carbon protonation of five phenylynamines (PhC≡CNH2, PhC≡CNHiPr, PhC=CNHC6F5, PhC≡CN(CH2CH2CN)2, and PhC≡CNMeC6F5) were determined in concentrated aqueous perchloric acid solution and the data were analyzed by the Cox–Yates method using the X0 acidity function. The extrapolated hydronium-ion catalytic coefficients so obtained are consistent with values measured directly in dilute acid solution, and the slopes of the Cox-Yates plots are similar to predictions made with the aid of Marcus rate theory for reactions originating from free ynamine initial states but unlike those predicted for reactions starting from nitrogen-protonated ynammonium ion initial states. This shows that none of these phenylynamines are protonated in even the most acidic solutions used (4 M) and sets new upper limits as low as pKa ≤ −3.1 for the conjugate acids of these ynamines. Comparison of the pKa limit for PhC≡CNH3+ with a literature value for the corresponding saturated compound, PhCH2CH2NH3+, gives a base-weakening effect for the phenylethynyl group of at least 12.5 pK units. Key words: acetylenic amines, concentrated acids, X0 excess acidity scale, Cox-Yates method, Marcus rate theory.

Aminoalkylidene and aminoalkyl derivatives of 6,11-dihydrodibenzo[b,e]thiepin-2- and -9-carbonitrile and 4,10-dihydrothieno[2,3-c]-1-benzothiepin-6-carbonitrile; Antidepressants with a new activity profile

Starting from the bromo ketones VIIc, XIII, and XXIV and proceeding via the alcohols VIIIc, IXc, XIV, XVII, and XXVI, the olefinic compounds IIc (+ VI), Xc (+XI), XVc and XIXc(+XXc), and the saturated compound XVIc were prepared. The pairs of geometrical isomers were separated by crystallization of salts and the individual compounds Iic, Xc, XVc, XVIc, XIXc, and XXc were transformed by treatment with cuprous cyanide in hexamethylphosphoric triamide to the corresponding cyano compounds IIb, Xb, XVb, XVIb, XIXb, and XXb. Compound IIb was synthesized also from the ketone VIIc via the cyano ketone VIIb and the cyano carbinol VIIIb. The secondary amine IIIb was prepared from IIc by partial demethylation with ethyl chloroformate, the following hydrolysis to IIIc, protection of NH group with butyrolactone, the following treatment with cuprous cyanide, and deprotection by mild hydrolysis. The title compounds, which are the cyano analogues of antidepressants of the prothiadene series, showed in pharmacological and biochemical tests properties of potential antidepressants and more or less selective inhibitors of the 5-hydroxytryptamine uptake in the rat brain; at the same time they are rather strong central cholinolytics.

Nucleophilic and acid-catalyzed cleavage of the cyclopropane rings of β,γ-unsaturated α-spirocyclopropyl ketones

Treatment of isophorone (8) with sodium amide and 1,2-dibromomethane gives 6,6-dimethyl-8-methylenespiro[2.5]octan-4-one (9) and 6,6,8-trimethylspiro[2.5]oct-7-en-4-one (10); similar treatment of 3-methylcyclohex-2-en-1-one (5) gives analogous spiro compounds 6 and 7 together with 8-methylenedispiro[2.1.2.3]decan-4-one (11) and 8-methyldispiro[2.1.2.3]dec-8-en-4-one (12). The spiro ketones 6, 7, 9, and 10 undergo homoconjugate nucleophilic addition on being heated in morpholine with cleavage of the cyclopropane rings to give 2-[2-(4-morpholinyl)ethyl]cyclohex-2-en-1-ones. The rates of reaction are much greater for the exo methylene compounds 6 and 9 than for their endo isomers 7 and 10, but the rate of reaction of 10 is only slightly greater than that of the corresponding saturated compound, 6,6,8-trimethylspiro[2.5]octan-4-one (15). A corresponding rate differential between 9 and 10 is observed in their reactions with isophorone (8) and sodium hydride to give 2,2′-(ethanediyl)bis[3,5,5-trimethylcyclohex-2-en-1-one] (18). The acceleration in the cases of 6 and 9 relative to that of 15 is attributed to spiroactivation by both the carbonyl and exocyclic ethylenic groups; the much smaller effect of the endocyclic ethylenic groups in the cases of 7 and 10 is ascribed to torsional strain in the transition states for ring opening. The spiro ketones 6, 7, 9, and 10 also undergo acid-catalyzed cyclopropane ring cleavage in ethanol, giving 2-(2-ethoxyethyl)cyclohex-2-en-1-ones. Again the exo methylene compounds 6 and 9 react much more rapidly than their endo isomers 7 and 10; this is considered to be due to factors analogous to those operative in the nucleophilic addition reactions and/or the more rapid protonation of the exo methylene compounds.

Cyclophanes. XII* The Synthesis of [2,2](3,3')Biphenylo(3,6)-phenanthrenophanes and Attempted Conversions into Hepta[8]circulene

[2,2](3,3')Biphenylo(3,6)phenanthrenophane-1,15-diene (6) has been synthesized by a ring-contraction procedure from the dithiacyclophane (10). The corresponding saturated compound (5) was prepared by pyrolysis of the sulfone (12). The stereochemistry of both (5) and (6) in solution has been determined to be syn from spectral evidence and neither compound shows any evidence of conformational ring-flipping or extensive mobility. Several attempts to convert the diene (6) into hepta[8]circulene are recorded. The factors affecting the photochemical ring-closures of cyclophanedienes are discussed.