Using Intelligent/Random Library Screening To Design Focused Libraries for the Optimization of Homogeneous Catalysts:  Ullmann Ether Formation

Abstract

A 96-member “pyridine” library consisting of both rationally chosen and “random” members was used to screen Ullmann ether forming reactions. The reaction of 2-bromo-4,6-dimethylaniline and other substrates with a variety of alkoxides was investigated under different conditions with the aid of an automated liquid handler. From the results of the 96-member library screening, a structure activity profile was determined which led to the design of smaller “focused” ligand libraries. The focused libraries produced a higher frequency of hits compared to the original 96-member library. Some of the more effective ligands discovered in this work were found to be generally useful for alkoxylation of a variety of substrates, and also functioned in intramolecular ether forming reactions. This work demonstrates for homogeneous catalysis the analogy to the pharmacological model of drug discovery. By using a large library to screen for a lead compound followed by screening the diversity space closest to the lead, a larger fraction of increased performance ligands was discovered.

Copper(I) Phenoxide Complexes in the Etherification of Aryl Halides

“…The phenyl allyl ether formed from reactions of complex 5 in [D 6 ]DMSO contained 30-66% deuterium, depending on the particular experiment. Therefore, the origin of all of the reducing equivalents is not certain, but the DMSO solvent is one source.…”

“…of such ligands include phenanthrolines, [3,4] N,N-dimethyl glycine, [5] various pyridine derivatives, [6] β-diketones, [7] and 1,1,1-tris(hydroxymethyl)ethane. [8] Despite the progress toward improving the scope and developing milder reaction conditions for the coupling of aryl halides with phenoxides, a mechanistic basis for the relative reactivities of different catalysts toward various C-O coupling processes has not been established.…”

“…(6)]. The low yield, presumably, results from (6) the steric hindrance of the pseudo-ortho substituent in the naphthalene substrate. The higher reactivity of the bromoarene among this pair of haloarenes, nevertheless, argues against an outer-sphere electron-transfer pathway to form aryl radical anions that dissociate a halide to form aryl radicals, either free or in a solvent cage.…”

Understanding the Heteroatom Effect on the Ullmann Copper-Catalyzed Cross-Coupling of X-Arylation (X = NH, O, S) Mechanism

“…These drawbacks were overcome at the beginning of the new century with the introduction of the ancillary chelating ligands (L) approach by the groups of Taillefer [12] and Buchwald [13] representing thus a major breakthrough in copper chemistry. The use of bidentate ligands like phenanthroline [14][15][16][17][18], diamines [19][20][21], amino acids [22][23][24], and 1,3-diketones [25,26] among others [27][28][29][30] has not only met the demands of reliability, mildness, and functional group tolerance but also interesting modern features such as orthogonal reactivity [26]. The applications so far known have been spread over a diverse range of areas from pharmaceutical [31] and natural products [32][33][34] to materials fields [35,36].…”

In Silico Design in Homogeneous Catalysis Using Descriptor Modelling

“…These include catalysts for oxidations reactions, [2] Suzuki, [3,4] Heck and Sonogashira cross-coupling, [4][5][6] Ullmann ether formation, [7] hydrogenation, [8] and cross-coupling via C-H activation [9,10]. Table 1 shows some examples of catalysts and reaction conditions that were optimized by high-throughput screening techniques.…”