A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1 x 10(5) units/m2. The dose was escalated up to 16 x 10(5) units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16 x 10(5) units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12 x 10(5) units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5 x 10(5) units/m2.

Deprotonative directed ortho cupration of aromatic/heteroaromatic C-H bond and subsequent oxidation with t-BuOOH furnished functionalized phenols in high yields with high regio- and chemoselectivity. DFT calculations revealed that this hydroxylation reaction proceeds via a copper (I → III → I) redox mechanism. Application of this reaction to aromatic C-H amination using BnONH2 efficiently afforded the corresponding primary anilines. These reactions show broad scope and good functional group compatibility. Catalytic versions of these transformations are also demonstrated.

Various aryl-, alkenyl-, and/or alkyllithium species reacted smoothly with aryl and/or benzyl ethers with cleavage of the inert C-O bond to afford cross-coupled products, catalyzed by commercially available [Ni(cod) ] (cod=1,5-cyclooctadiene) catalysts with N-heterocyclic carbene (NHC) ligands. Furthermore, the coupling reaction between the aryllithium compounds and aryl ammonium salts proceeded under mild conditions with C-N bond cleavage in the presence of a [Pd(PPh ) Cl ] catalyst. These methods enable selective sequential functionalizations of arenes having both C-N and C-O bonds in one pot.

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Direct catalytic transposition of allylic alcohols is a powerful approach to the synthesis of complex hydroxylated organic compounds.1 Several transition metal catalysts have been developed for this purpose, including vanadium,2 molybdenum,2 and rhenium reagents. 3 Among these, rhenium(VII) oxide and triphenylsilyl perrhenate have been found to be superior in terms of reactivity and chemoselectivity, displaying high activity at low temperatures with no competitive oxidation observed with some of the other catalysts. One drawback of the reversible process (eq 1) is a general lack of regioselectivity; 4 stereoselectivity in the transposition of primary allylic alcohols is also low.(1)In this communication, we describe a practical method that allows for control of the regioand stereoselectivity in the rhenium-catalyzed transposition of allylic alcohols, expanding the scope of the reaction for the stereoselective synthesis of complex molecules. 5 In our initial experiments, rearrangement of substrate 1 in the presence of Re 2 O 7 (2.5 mol %) occurred with low regio-and stereoselectivity as expected, delivering 2 with 60% conversion as a 3:2 mixture of diastereomers (Scheme 1). We hypothesized that the reaction medium must be slightly acidic due to formation of a catalytic amount of perrhenic acid (pK a = 1.25) 6 upon interaction of rhenium(VII) oxide with the substrate and/or adventitious water. 7 In the presence of a catalytic acid the rearranged product can in principle be trapped as an acetal or ketal, and then the 1,3-syn diastereomer should be favored on thermodynamic grounds. Remarkably, upon exposure of 1 to benzaldehyde dimethyl acetal and Re 2 O 7 (2.5 mol %), essentially a single product was formed in 94% yield after 20 h at room temperature. Thus, the rhenium catalyst performs a dual catalytic function as a transition metal catalyst for the hydroxyl group transposition and as an acid catalyst for acetal formation.Screening of the reaction parameters demonstrated that although a number of solvents can be used (toluene, Et 2 O, THF, CH 2 Cl 2 ), 8 dichloromethane provides the best results in terms © XXXX American Chemical Society *zakarian@chem.ucsb.edu . Supporting Information Available: Experimental procedures, copies of 1 H and 13 C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. of reaction rate. Typically, reactions are characterized by a rapid formation of a diastereomeric mixture of rearranged diol acetals (within ~20 min at room temperature) followed by slow equilibration of the acetals to the 1,3-syn product (3). NIH Public AccessThe influence of reaction time with alternative rhenium catalysts is summarized in Table 1. With all three catalysts studied, methyltrioxorhenium (MTO), Ph 3 SiOReO 3 , and Re 2 O 7 , the rearrangement/acetalization was complete within 3 h at room temperature. As expected, MTO is the least reactive catalyst. 2c,9 Notably, with all of the three rhenium catalysts the initial acetal formation was followed by equilibration to 3....