Ruthenium-Catalyzed Synthesis of Aryl and Alkenyl Halides from Fluorosulfonates.

Aryl and alkenyl halides are widely used as key intermediates in organic synthesis, particularly for the formation of organometallic reagents or as radical precursors. They are also found in pharmaceutical and agrochemical ingredients. In this work, the synthesis of aryl and alkenyl halides from the corresponding fluorosulfonates using commercially available ruthenium catalysts is reported. Notably, this is the first conversion of phenols to aryl halides that is efficient with chloride, bromide, and iodide. Fluorosulfonates are readily prepared using sulfuryl fluoride (SO2 F2 ) and less expensive substitutes for triflates. Although aryl fluorosulfonates and their reactions are well known, this is the first report of an efficient coupling of alkenyl fluorosulfonates. To finish, it was demonstrated, by means of representative examples, that the reaction is possible in a one-pot process, starting directly from phenol or aldehyde.

New Chemical Transformations Involving SO2 F2 -Mediated Alcohol Activation.

Sulfuryl fluoride is a gas produced on a multi-ton scale for its use as a fumigant. In the last decades, it has gained interest in organic synthesis as a reagent with unique properties in terms of stability and reactivity when compared to other sulfur-based reagents. Sulfuryl fluoride has not only been used for sulfur-fluoride exchange (SuFEx) chemistry but also encountered applications in classic organic synthesis as an efficient activator of both alcohols and phenols, forming a triflate surrogate, namely a fluorosulfonate. A long-standing industrial collaboration in our research group drove our work on the sulfuryl fluoride-mediated transformations that will be highlighted below. We will first describe recent works on metal-catalyzed transformations from aryl fluorosulfonates while emphasizing the one-pot processes from phenol derivatives. In a second section, nucleophilic substitution reactions on polyfluoroalkyl alcohols will be discussed and the value of polyfluoroalkyl fluorosulfonates in comparison to alternative triflate and halide reagents will be brought to light.

Traceless N-Polyfluoroalkylation of Weakly Nucleophilic Nitrogen Containing Compounds.

Here we report an efficient access to high-value N-polyfluoroalkyl anilines, primary polyfluoroalkylamines and N,N-bis(polyfluoroalkyl)amines, via N-polyfluoroalkylation of sulfonamides and phthalimide derivatives using sulfuryl fluoride (SO2 F2 ). The in situ formation of polyfluoroalkyl fluorosulfonates from commercially available fluorinated alcohols and economical sulfuryl fluoride is highly advantageous given that some polyfluoroalkyl halides are ozone-depleting substances (ODS) regulated by the Montreal protocol. This general method is applied to the polyfluoroalkylation of a variety of sulfonamides, N-sulfonyl carbamates and phthalimide with a wide tolerance of functional groups. The process thus provides viable access for industry to N-(polyfluoroalkyl)anilines as well as primary and secondary N-(polyfluoroalkyl)amines, which are very valuable but not easily accessible building blocks for life science applications.

SO2F2-Mediated N-Alkylation of Imino-Thiazolidinones.

The N-alkylation of ambident and weakly nucleophilic imino-thiazolidinones has been developed via substitution with alkyl fluorosulfonates. These reactive electrophiles are obtained through the transformation of nontoxic, economic, and commercially available alcohol derivatives on exposure to SO2F2 gas. The use of electron-withdrawing groups and DMAc as solvent affords a (Z)- and N-endocyclic selectivity for the easy introduction of a variety of alkyl and polyfluoroalkyl chains.

Synthesis of P-Substituted 5- and 6-Membered Benzo-Phostams: 2,3-Dihydro-1H-1,2-benzazaphosphole 2-Oxides and 2,3-Tetrahydro-1H-1,2-benzazaphosphinine 2-Oxides.

Several approaches were developed for the preparation of phosphorus-substituted 5- and 6-membered benzophostams. Carbodiimide-promoted cyclization of zwitterionic aminophosphinates derived from a nitrobenzene precursor accomplished the cyclization in good yields. Alternatively, a novel copper-catalyzed cross-coupling between a phosphonamide and a bromobenzene precursor produced the heterocycles in moderate to good yields. Three different methods are compared for the synthesis of the P-ethoxy-substituted 5-membered benzophostam.

Synthesis of 3-Amino-5-fluoroalkylfurans by Intramolecular Cyclization.

A synthesis to access rarely described 3-amino-5-fluoroalkylfurans has been developed by cyclization of easily accessible fluorovinamides. This method is rapid and simple and affords the desired furans as hydrochloride salts in quantitative or nearly quantitative yields. It is compatible with four different fluorinated groups (-CF3, -CF2CF3, -CHF2, and -CF2Cl) and a wide range of substituents on the amine.

Validating the use of fecal glucocorticoid metabolite analysis to assess the adrenocortical activity of the zoo-housed Sichuan takin (Budorcas taxicolor tibetana).

With limited information known about the zoo-housed Sichuan takin (Budorcas taxicolor tibetana), there is a need to gain more knowledge about their basic physiology to be able to better assess their well-being. Our goal was to develop noninvasive methods to evaluate stress physiology in the Sichuan takins housed under human care. The objectives were: (1) validate the use of fecal glucocorticoid metabolite (FGM) analysis to monitor adrenocortical activity and (2) determine the relationship between FGM concentrations and changes in various factors including environmental conditions, reproductive hormones, and social factors. Three (one male and two females) adult Sichuan takins were included in the study from Lincoln Park Zoo. A cortisol enzyme immunoassay was used to analyze FGM from samples that were collected 2-4 times per week. FGM was biochemically validated in the laboratory and biologically validated using pregnancy and parturition. Results showed that 1 day after birth one female had a more than a six-fold increase in FGM. A positive relationship (p < .05) was observed between FGM and temperature for two of the three takins. Finally, FGM values tended to increase during times when aggression (p = .09) and reproductive (p = .08) behaviors were observed. In conclusion, environmental, reproductive, and behavioral factors could affect adrenocortical activity in zoo-housed Sichuan takins; therefore, these methods can be used to assist in the management and conservation of this threatened species both in zoos and potentially in the wild.

Deprotonative Functionalization of the Difluoromethyl Group.

The functionalization of 3-(difluoromethyl)pyridine has been developed via direct deprotonation of -CHF2 with a lithiated base and subsequent trapping with various electrophiles in THF. In situ quenching gives access to 3-pyridyl-CF2-SiMe2Ph as a new silylated compound, which can be postfunctionalized with a fluoride source to obtain a larger library of 3-(difluoroalkyl)pyridines that could not be accessed via direct deprotonation.

Characterizing adrenocortical activity in zoo-housed southern three-banded armadillos (Tolypeutes matacus).

Improving the husbandry in the southern three-banded armadillo (Tolypeutes matacus) through gaining knowledge of its stress physiology is imperative to maintaining a healthy, zoo-housed population. Our objectives were to: 1) validate the use of fecal hormone analysis for monitoring adrenocortical activity using both an adrenocorticotropic hormone (ACTH) challenge and biological events; and 2) characterize longitudinal adrenocortical activity in male and female southern three-banded armadillos. An ACTH injection was given intra-muscularly to one male (4IU/kg; 5.6IU total) and one female (5.5IU/kg; 8IU total) southern three-banded armadillo. Fecal samples were collected 1 day pre- and continued 5 days post-ACTH to capture the physiological response measured by elevated fecal glucocorticoid metabolites (FGM) to validate these techniques. Additionally, natural and routine events, including pairing individuals for breeding and veterinary procedures/handling, were used to biologically validate these techniques. To characterize adrenocortical activity, fecal samples (∼3025 total; n=275/animal/yr) were collected from 11 (5 males; 6 females) southern three-banded armadillos 5-7 times a week for 1 year at Lincoln Park Zoo (Chicago, IL). A cortisol enzyme immunoassay was used for FGM analysis. The ACTH challenge in the male resulted in a twofold increase of FGM (1123.2±36.2 ng/g dry feces) above baseline (675.7±10.0 ng/g dry feces) at approximately 54-94h post- injection. The female exhibited a twofold increase (1635.4 ng/g dry feces) over baseline FGMs (608.5±12.3 ng/g dry feces) approximately 30h post-injection. Reproductive behaviors and veterinary procedures resulted in elevated FGM concentrations from all individuals except for one male. The longitudinal characterization demonstrated that sex and season did not influence (P<0.05) FGM concentrations. Individuals were highly variable with mean FGM concentration of 2010.1±862.4 ng/g dry feces (range, 816.3-7889.1 ng/g dry feces). Mean FGM baseline concentration was 878.5±201.8ng/g dry feces (range, 475.2-1955.5 ng/g dry feces) with a mean elevated FGM concentrations of 2694.3±1111.4 ng/g dry feces (range, 1110.3-10,683.3 ng/g dry feces). This study provides the foundation for future research on how the environment directly affects the adrenocortical activity in this species of armadillo.

Improved procedure for the synthesis of enamine N-oxides.

An improved procedure for the preparation of enamine N-oxides involving aminolysis of epoxides, chlorination, N-oxidation, and dehydrochlorination is described. Although isolated beta-chloroamine N-oxides are prone to rearrangements when isolated, these side reactions can be slowed by the presence of stabilizing organic acids. The scope and limitations of this strategy are discussed.

Direct asymmetric catalytic 1,2-addition of RZnX to aldehydes promoted by AlMe3 and reversal of expected stereochemistry.

Addition of AlMe3 to commercial THF solutions of RZnX (R = aryl, functionalised aryl, vinyl; X = Br, I) simultaneously promotes Schlenk equilibria (leading to competent nucleophiles) and the formation of an Al-Zn-ligand catalyst delivering 80-90% ee for Ar(1)CH(OH)Ar(2) formation from aldehydes.