Palladium-catalyzed direct arylation reactions are described with a broad range of azine and azole N-oxides. In addition to aspects of functional group compatibility, issues of regioselectivity have been explored when nonsymmetrical azine N-oxides are used. In these cases, both the choice of ligand and the nature of the azine substituents play important roles in determining the regioisomeric distribution. When azole N-oxides are employed, preferential reaction is observed for arylation at C2 which occurs under very mild conditions. Subsequent reactions are observed to occur at C5 followed by arylation at C4. The potential utility of this methodology is illustrated by its use in the synthesis of a potent sodium channel inhibitor 1 and a Tie2 Tyrosine Kinase inhibitor 2.
Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are presented. The order of each reaction component is determined to provide a general mechanistic picture. The C-H bond cleaving step is examined in further detail through computational studies, and the calculated results are in support of an inner-sphere concerted metalation-deprotonation (CMD) pathway. Competition experiments were conducted with N-oxides of varying electronic characters, and results revealed an enhancement of rate when using a more electron-deficient species, which is in support of a CMD transition state. The effect of base on reaction rate was also examined and it was found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that Pd(OAc)(2) plays a pivotal role in the reaction mechanism as more than merely a precatalyst, but also as a source of acetate base required for the C-H bond cleavage step.
A method for enantioselective desymmetrization of 1,1-diborylalkanes through a stereoselective Pd-catalyzed Suzuki-Miyaura cross-coupling has been thoroughly optimized. The most effective ligand was found to be a α,α,α,α-tetra-aryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-derived phosphoramidite. Results show that in order to achieve high selectivity, a suitable balance between the sterics of the aryl groups and the amino group on the ligand must be achieved. While the base has been known to facilitate transmetallation in cross-coupling reactions, mechanistic studies on this desymmetrization process reveal that the base, in the presence of KHF2, likely plays an additional role in the hydrolysis of the pinacol boronates to the corresponding boronic acids. Through an in depth optimization of the chiral ligand and mechanistic studies, it was possible to obtain ee values over 90% for several aryl bromides and to develop a reliably scalable process (up to one gram of 1,1-diborylalkane substrate).
A method has been developed for the chemo- and stereoselective Suzuki-Miyaura cross-coupling of optically enriched gem-diboronyl compounds with various aryl bromides. Experimental evidence suggests that the Lewis acidity of the second boron group in these substrates plays a significant role in facilitating these otherwise challenging cross-coupling processes. β-Diboronyl esters may be successfully cross-coupled in excellent yield and enantiomeric excess with prior conversion of the pinacol boronate to the corresponding trifluoroborate salt. In contrast, a substrate bearing a Weinreb amide can undergo direct coupling of the Bpin moiety, likely due to the stronger coordination of the more basic amide carbonyl group. The resulting optically enriched secondary boronate may be used in a second enantioselective cross-coupling to afford pharmaceutically relevant diarylmethane products. The use of a Weinreb amide substrate allows for facile postcoupling modification, as demonstrated by a transformation to the corresponding ketone.
In the presence of optimized palladium/phosphine catalyst systems, about 100 examples of the desired products are synthesized. The scope and functional group compatibilities for substituted pyridine and quinoline N-oxides are studied, and the conditions for the regioselective arylation of isoquinoline and 3-substituted pyridine N-oxides are evaluated. In the latter cases, both the choice of ligand and the nature of the azine substituents play important roles in the regioselectivity. Deoxygenation procedures [cf. for example conditions B) in Part 1] are studied and can also applied to obtain separable regioisomers from arylated isoquinoline N-oxides (to be continued). -(CAMPEAU, L.-C.; STUART, D. R.; LECLERC, J.-P.; BERTRAND-LAPERLE, M.; VILLEMURE, E.; SUN, H.-Y.; LASSERRE, S.; GUIMOND, N.; LECAVALLIER, M.; FAGNOU*, K.; J. Am. Chem. Soc. 131 (2009) 9, 3291-3306; Cent. Catal. Res. Innov., Univ. Ottawa, Ottawa, Ont. K1N 6N5, Can.; Eng.) -Klein 27-083
Process analytical technology (PAT; Raman spectroscopy and FBRM) was used to monitor the salt formation step of a development compound in real time. The data obtained were used to understand the crystallization kinetics and behavior. A mechanistic model was proposed on the basis of the sequence of events, and the mechanism was verified by the Raman profiles. Several operational parameters were studied in a matrix setting in order to identify the factors that affect the quality attributes of the final product such as particle size and morphology. The kinetic characterization through PAT revealed that the process is primarily influenced by temperature and solvent composition and that the acid addition rate and agitation speed were found to have a marginal effect. A regression model on API particle size was extracted from the data set, and its accuracy was verified at various set points of the parameter range covered in the investigation. The workflow adopted by this study illustrates how process knowledge generated by a combination of PAT and modeling, as well as a multistaged experimental plan executed on the basis of learning from technical insight, can efficiently lead to the process control as required under the current regulatory frameworks.
Up, up and away: Energy up-conversion, the generation of a high-energy excited state by absorption of two lowenergy photons, is an emerging technique with possible applications in different fields, such as harnessing red or infrared solar photons to power photovoltaic devices. COMMUNICATIONS . 9566 -9570Nickel-Catalyzed C À P Cross-Coupling by C À CN Bond Cleavage Prosperous coupling: A nickel-catalyzed CÀP cross-coupling reaction with Me 3 SiPPh 2 by carbon-cyano bond cleavage has been developed. This method is characterized by its simplicity and wide application to the synthesis of various monophosphorus and P,N bidentate ligands (see scheme). Unprotected synthesis: The first enantioselective chiral phosphoric acid catalyzed transfer hydrogenation of unprotected ortho-hydroxybenzophenone NÀH imines by using a Hantzsch ester as the hydrogen source afforded the corresponding chiral N,O-unprotected ortho-hydroxydiarylmethyl-A C H T U N G T R E N N U N G amines in high yields with excellent enantioselectivities (see scheme). Clearing the air! By using a balloon pressure of CO, the direct oxidative carbonylation of various heteroarenes with different alcohols was achieved in good to high yields with air as the oxidant in the presence of PdCl 2 A C H T U N G T R E N N U N G (PPh 3 ) 2 (see scheme). Notably, this transformation was carried out under base-free conditions. The reaction showed remarkably high regioselectivity and presents an environmentally benign protocol for the synthesis of carboxylic acid derivatives. Domino Reactions Continuous-Flow ChemistryH. E. Bartrum, D. C. Blakemore, C. J. Moody,* C. J. Hayes* . . -9589Rapid Access to a-Alkoxy and a-Amino Acid Derivatives through Safe Continuous-Flow Generation of Diazoesters Microreactors: A highly efficient continuous-flow process has been developed for the synthesis of diazoesters from arylsulfonylhydrazones by means of in-flow Bamford-Stevens reactions. Furthermore, a range of a-alkoxy and a-amino acid derivatives have been prepared in excellent yields through rhodium(II)-mediated O À H and N À H insertions, without the need to isolate or handle the potentially hazardous diazo species (see scheme). . 9590 -9594Multivalued Logic Gates Based on DNA Alternative concept of logic: The ensemble of DNA on the surface of silica nanoparticles could be used to design ternary logic gates, which go beyond common binary operations. Herein, by assigning more than two possible states to input and output signals, thereby implementing multivalued logic, the densities of information can be increased (see scheme). Go with the flow! A method for conversion of keto halides to lactams by means of sequential azidation and intramolecular Schmidt reaction in a combined flow format is described (see scheme; MWI = microwave irradiation, TFA = trifluoroacetic acid). Continuous-Flow Chemistry(Ln = La (1), Tb (2), saOH 2 = salicylaldoxime) were synthesized by a twostep self-assembly process from MnCl 2 , saOH 2 , and LnA C H T U N G T R E N N U N G (NO 3 ) 3 under basic conditions i...
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