Ligand synthesis nucleophilic substitution

Sulfoximines bearing a chiral sulfur atom have recently emerged as valuable ligands for metal-catalysed asymmetric synthesis.In particular, C2-symmetric bis(sulfoximines), such as those depicted in Scheme 1.51, were applied to the test reaction, achieving enantioselectivities of up to 93% ee. The most selective ligand (R = c-Pent, R = Ph) of the series was also applied to the nucleophilic substitution reaction of l,3-diphenyl-2-propenyl acetate with substituted malonates, such as acetamido-derived diethylmalonate, which provided the corresponding product in 89% yield and 98% ee. 

An example of a direct (one-step) preparation involving aliphatic nucleophilic substitution with [ F]fluoiide is the synthesis of [ F]fallypride (Scheme 34), a high-affinity dopaminergic D2 receptor ligand, from the corresponding tosylate in about 20% radiochemical yield [145],... 

The general synthesis of the Daniphos ligands starting from enantiomerically pure [(R)-l-(phenylethyl)dimethylamine]chromiumtricarbonyl 1, is depicted in Scheme 1.4.1 [15]. A directed ortho-metallation (DOM) and subsequent quench with a chlorophosphine leads to an enantiomerically pure planar-chiral complex, which after chlorination using ACE chloride (1-chloroethyl chloroformate) is transformed into the desired diphosphine by a nucleophilic substitution without any loss of optical purity (Scheme 1.4.1) [6, 10]. 

Although this catalytic reaction appeared to be of synthetic interest, it has since then neither been applied in synthesis nor further developed. This might be attributed in part to problems with reproducibility and catalyst stability under the reaction conditions, although the Hieber complex was used in a stoichiometric manner for the preparation of a variety of 7i-allyl-Fe complexes. These latter compounds served as starting materials for a plethora of subsequent reactions [34]. The results obtained by Nakanishi and coworkers on the stability and reactivity of n-allyl-Fe-nitrosyl complexes proved such intermediates to be reactive towards a variety of nucleophiles however, the Fe complexes formed upon nucleophilic substitution were catalytically inactive. Hence, in order to maintain the catalytic activity, the formation of intermediate 7i-allyl-Fe complexes had to be circumvented. About 3 years ago we started our research in this field and envisioned the use of a monodentate ligand to be a suitable way to stabilize the proposed catalytically active G-allyl complex. The replacement of one CO by a non-volatile basic ligand was thought to prevent the formation of the catalytically inactive 7t-allyl-Fe complex (Scheme 7.21). 

Fluoroarene-Cr(CO)2L complexes 33p [L = CO, PPh3, P(OPh)3, P(pyrrolyl)3, P(pyrolyl)2 (NMeBn)], where L is a potential linker ligand for solid-phase synthesis, have been evaluated with regard to the rates of nucleophilic substitution by amines [35]. The preparative and kinetic results indicate that SNAr reactions on tris(pyrrolyl)phosphine-modified fluoroar-enechromium complexes proceed rapidly and with high efficiency, and are thus appropriate for the development of solid-phase versions for use in combinatorial synthesis (Scheme 18). 

A wide variety of nucleophiles add to an -rf-allyl ligand. Desirable nucleophiles typically include stabilized carbanions such as CH(COOR)2 or 1° and II0 amines. Unstabilized nucleophiles such as MeMgBr or MeLi often attack the metal first and then combine with the n-allyl by reductive elimination. The Tsuji-Trost reaction, which is typified by the addition of stabilized carbanions to T 3—allyl ligands complexed to palladium followed by loss of the resulting substituted alk-ene, comprises an extremely useful method of constructing new C-C bonds, and many applications of this reaction have appeared in the literature.61 Equation 8.43 illustrates an example of a Pd-catalyzed addition of a stabilized enolate to an allyl acetate.62 The initial step in the catalytic cycle is oxidative addition of the allyl acetate to the Pd(0) complex, followed by nq1 to nq3—allyl isomerization, and then attack by the nucleophile to a terminal position of the T 3—allyl ligand. We will discuss the Tsuji-Trost reaction, especially in regard to its utility in chiral synthesis,63 more extensively in Chapter 12. 

We have seen how pyridine /V-oxidcs can be used to promote electrophilic oxidation at C-2,4, and 6. They also promote ort/zo-lithiation and nucleophilic substitution making them very versatile intermediates. This is well illustrated in Queguiner s synthesis of the antibiotic caerulomy-cins. 2,2 -Bipyridyl, available as a ligand for many metals, is easily oxidised to its monoxide 146. The synthesis starts with two electrophilic substitutions. Lithiation occurs ortho to the /V-oxidc quenching with BrCN gives a good yield of the bromide 147 and a conventional electrophilic nitration occurs para to the /V-oxidc. 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

There are several efficient methods available for the synthesis of homochiral sulfoxides [3], such as asymmetric oxidation, optical resolution (chemical or bio-catalytic) and nucleophilic substitution on chiral sulfinates (the Andersen synthesis). The asymmetric oxidation process, in particular, has received much attention recently. The first practical example of asymmetric oxidation based on a modified Sharpless epoxidation reagent was first reported by Kagan [4] and Modena [5] independently. With further improvement on the oxidant and the chiral ligand, chiral sulfoxides of >95% ee can be routinely prepared by these asymmetric oxidation methods. Nonetheless, of these methods, the Andersen synthesis [6] is still one of the most widely used and reliable synthetic route to homochiral sulfoxides. Clean inversion takes place at the stereogenic sulfur center of the sulfinate in the Andersen synthesis. Therefore, the key advantage of the Andersen approach is that the absolute configuration of the resulting sulfoxide is well defined provided the absolute stereochemistry of the sulfinate is known. 

Solid-liquid phase transfer catalyst 2 for aliphatic and aromatic nucleophilic substitution synergistic effect with Cu in Ullmann synthesis as ligand in homogeneous hydrogenation catalysis (see 1st edition). 

A series of new phosphinooxazoline ligands have been recently prepared and tested in the asymmetric Heck reaction. Synthesis of the ligands involved the aromatic nucleophilic substitution of aryl fluorides with phosphide nucleophile generated from the corresponding phosphine and KHMDS (eq 49). The reaction proceeded in good yields, but proved to be more sluggish with electron-rich aryl fluorides and failed completely when the addition of electron-deficient phosphines was attempted. 

Oliana M, King F, Horton PN, Hursthouse MB, Hii KK (2006) Practical synthesis of chiral vinylphosphine oxides by direct nucleophilic substitution. Stereodivergent synthesis of aminophosphine ligands. J Org Chem 71 2472-2479... 

The 1,2,4-triazines usually attract much greater attention than their 1,2,3-relatives. Due to the abundance of nitrogen atoms in the cycle and electron deficiency, they are widely explored in reactions of nucleophilic substitution, inverse-electron-demand DA cycloaddition and other ring transformations, as coordinating ligands for metal ion binding and bioactive agents. So, the points of interest involve 1,2,4-triazine synthesis, their transformation and functionalization, and further studies for different applications. 

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