Copper PYBOX

The iron-catalyzed process can also be performed with iron-PYBOX systems, as reported by Redlich and Hossain [29]. The PYBOX ligands are powerful tools in organic synthesis. However, for the iron-catalyzed synthesis of aziridines (Scheme 9.14), the results are not as convincing as for similar copper-PYBOX systems. Not only are the yields moderate (up to 54%), but also the enantiomeric excesses (up to 49%) are not in a synthetically useful range, which precludes their use in elaborate applications. 

Perhaps the most elegant and attractive method to control absolute stereochemistry, however, is the use of asymmetric catalysis, and several examples of this approach have been applied to the Nazarov cyclization. Traimer and co-workers were the first to report a single example of a successfiil asymmetric Nazarov cyclization catalyzed by chiral scandium complex in 2003. In the exact same issue of the journal however, Aggarwal and co-workers reported a more in-depth study using copper pyBOX complexes. ... 

Scheme 5.67 Evans Mukaiyama aldol and vinylogous aldol reactions mediated by the copper PYBOX catalyst 217 enantioselective synthesis of callipeltoside A building block 225.

The bench-stable dihydrate of the copper PYBOX catalyst 217 served to mediate the vinylogous Mukaiyama aldol addition of dienolate 224 to para-methoxybenzyloxyacetaldehyde 219b. After first attempts were discouraging... 

Evans et al. reported that the his(oxazolinyl)pyridine (pybox) complex of copper(II) 17 is a selective catalyst of Diels-Alder reactions between a-bromoacrolein or methacrolein and cydopentadiene affording the adducts in high enantioselectivity [23] (Scheme 1.30). Selection of the counter-ion is important to achieve a satisfactory reaction rate and enantioselectivity, and [Cu(pyhox)](ShFg)2 gave the best result. This catalyst is also effective for the Diels-Alder reaction of acrylate dieno-philes (vide infra). 

Ghosh et al. [70] reviewed a few years ago the utihty of C2-symmetric chiral bis(oxazoline)-metal complexes for catalytic asymmetric synthesis, and they reserved an important place for Diels-Alder and related transformations. Bis(oxazoline) copper(II)triflate derivatives have been indeed described by Evans et al. as effective catalysts for the asymmetric Diels-Alder reaction [71]. The bis(oxazoline) Ugand 54 allowed the Diels-Alder transformation of two-point binding N-acylimide dienophiles with good yields, good diastereos-electivities (in favor of the endo diastereoisomer) and excellent ee values (up to 99%) [72]. These substrates represent the standard test for new catalysts development. To widen the use of Lewis acidic chiral Cu(ll) complexes, Evans et al. prepared and tested bis(oxazoHnyl)pyridine (PyBOx, structure 55, Scheme 26) as ligand [73]. 

CuOTf/PyBox System The first direct asymmetric addition of alkynes to imines, generated from aldehydes and amines in situ, was reported by using copper salts in the presence of chiral PyBox ligand (Scheme 5.2). The products were obtained in good yields and excellent enantioselectivities in most cases. When toluene was used as solvent, up to 93% yield and 99% ee were obtained. Up to 99.5% ee was obtained when the reaction was carried out in 1,2-dichloroethane. The reaction can also be performed in water smoothly, and good enantioselectivities (78-91% ee) were obtained. 

Considerable variation in stereocontrol can also occur, depending on the catalyst employed (equation 125). In general, the various rhodium(II) carboxylates and palladium catalysts show little stereocontrol in intermolecular cyclopropanation162,175. Rhodium(II) acetamides and copper catalysts favour the formation of more stable trans (anti) cyclopropanes162166. The ruthenium bis(oxazolinyl)pyridine catalyst [Ru(pybox-ip)] provides extremely high trans selectivity in the cyclopropanation of styrene with ethyl diazoacetate43. Furthermore, rhodium or osmium porphyrin complexes 140 are selective catalysts... 

Allylic oxidation of a variety of cyclic alkenes with copper complexes of different pybox ligands (8) and with various peresters shows high enantioselectivity (80-96% ee). Use of phenylhydrazine as an additive and acetone as solvent accelerates the reaction. It has been suggested that the phenylhydrazone is responsible for the observed acceleration. Using EPR spectra, it has been shown that the Cu(II) species is reduced to Cu(I) by phenylhydrazine and phenylhydrazone. It has been found that the presence of a gem-diphenyl group at C(5) and a secondary or tertiary alkyl substituent at the chiral centre at C(4) of the oxazoline rings is crucial for high enantioselectivity. 

Subsequently copper-catalyzed ATRA reactions were developed continuously and the progress was reviewed thoroughly (reviews [281-286]). Therefore, only selected recent examples are highlighted here. A number of ligands (Fig. 55), such as TMEDA, aliphatic tri- and tetramines 214, 215, or 216, PyBOX derivatives 5, bipyridines 26, terpyridines 8, bis- or tris(2-pyridylmethyl)amines 217 and 218, picolinaldehyde imines 219, tris(pyrazolyl)borates 220, or thionophosphates 221 [287], were applied successfully. Phenanthrolines or the bis(TPMA) ligand (cf. Part 2, Fig. 13) also proved valuable to perform ATRA under mild conditions at... 

As for ACP, from 1986 to 1991, several nitrogen ligands of bidentate corrin mimics and bis(oxazoline) were successfully developed as chiral ligands with copper catalysts [23,24]. Pybox families reported by Singh et al. [25] resulted in good-to-excellent activity for ACP in combination with copper. 

Jorgensen et al. reported that C2-symmetric bis(oxazoline)-copper(II) complex 25 also acts as chiral Lewis acid catalyst for a reaction of allylic stannane with ethyl glyoxylate [37]. Meanwhile, p-Tol-BINAP-CuCl complex 26 was shown to be a promising chiral catalyst for a catalytic enantioselective allylation of ketones with allyltrimethoxysilane under the influence of the TBAT catalyst [38]. Evans and coworkers have developed (S,S)-Ph-pybox-Sc(OTf)3 complex 27 as a new chiral Lewis acid catalyst and shown that this scandium catalyst promotes enantioselective addition reactions of allenyltrimethylsilanes to ethyl glyoxylate [39]. But, when the silicon substituents become bulkier, nonracemic dihydrofurans are predominantly obtained as products of [3+2] cycloaddition. 

Both Diels-Alder and hetero-Diels-Alder reactions can be rendered stereoselective using l copper(II) salts, but inferior levels of stereoselection were observed relative to other pybox derivatives. Lanthanide-catalyzed 1,3-dipolar cycloaddition also exhibited moderate (61%) enantioselection. ... 

Mukaiyama aldol reactions catalyzed by the pybox-copper complex 65 lead to high enantiocontrol with a range of nucleophiles adding to benzyloxy acetaldehyde [44]. As shown in Scheme 9-22, catalyst 66 also led to high enantioselectiv-ities (up to 99% ee) on addition to various pyruvate esters to generate adducts 67 [45]. 

Copper complexes of chiral Pybox (pyridine-2,6-bis(oxazoline))-type ligands have been found to catalyze the enantioselective alkynylation of imines [26]. Moreover, the resultant optically active propargylamines are important intermediates for the synthesis of a variety of nitrogen compounds [27], as well as being a common structural feature of many biologically active compounds and natural products. Portnoy prepared PS-supported chiral Pybox-copper complex 35 via a five-step solid-phase synthetic sequence [28]. Cu(l) complexes of the polymeric Pybox ligands were then used as catalysts for the asymmetric addition of phenylacetylene to imine 36, as shown in Scheme 3.11. tBu-Pybox gave the best enantioselectivity of 83% ee in the synthesis of 37. 

Li and co-workers examined a variety of ligands such as chiral bisoxazolines, Quinap, and Binap as ligands in conjugation with various copper salts. Li found that CuOTf with PyBox provided the best results for 29 and found that aromatic substituted alkynes gave the best yields and enantioselectivity relative to the aliphatic substituted alkynes. Li also found that the presence of an ort/io-methoxy substituent improved enantioselectivity and attributed the improvement in selectivity to potential coordination of the oxygen atom to the copper/Ugand complex. 

High-energy vbratbnal micro miii QM-3A 1200rpm, stainless steel Jar (50mL), 2x12mm copper balls, substrate alkyne DDQ PyBox-1 1 1.1.1 0.1, silica gel. 

Reproduced from Li Z, Jiang Z, Su W. Fast, solvent-free, highly enantioselective three-component coupling of aldehydes, akynes, and amines catalysed by the copper(H)pybox complex under high-vibratbn ball-milling. Green Chem 2015 17 2330-4, with permission from the Royal Society of Chemistry. 

Bis-oxazolines (Box), azabis-oxazolines (azaBox) and pyridine bis-oxazoline (PyBox) with a C2 symmetry form the great majority of various oxazoline-derived ligands which are used in immobilized catalytic cyclopropanation reactions (Scheme 36). For these reactions, immobilized ruthenium and copper complexes which are able to form carbene intermediates have been tested. Most of the time, the reaction involved styrene and ethyl diazoacetate (EDA). However other alkenes (diphenyl ethylene. ..) and other diazo compounds (i.e. tertiobutyl and ethyl 2-phenyl diazoacetate) have also been investigated (Scheme 36). 

Portnoy focused his attention on the immobilization of PyBox ligands [153], The polymer-supported PyBox 240 were prepared in five steps from the Wang trichloroacetamidate resin (Scheme 96). The supported-ligands 240 were allowed to react with copper (1) triflate for 24h to afford the corresponding catalysts 241. These catalysts were then used in the first heterogeneous catalyzed addition of phenylacetylene to imine. 

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