Copper catalysts cycloadditions

Ethyl diazopyruvate, under copper catalysis, reacts with alkynes to give furane-2-carboxylates rather than cyclopropenes u3) (Scheme 30). What looks like a [3 + 2] cycloaddition product of a ketocarbenoid, may actually have arisen from a primarily formed cyclopropene by subsequent copper-catalyzed ring enlargement. Such a sequence has been established for the reaction of diazoacetic esters with acetylenes in the presence of certain copper catalysts, but metallic copper, in these cases, was not able to bring about the ring enlargement14). Conversely, no cyclopropene derivative was detected in the diazopyruvate reaction. 

The second well-known and much-used carbon-carbon bond forming reaction is a [4 + 2]-cycloaddition, the Diels Alder reaction. Very many chiral Lewis acid catalysts have been used to promote this reaction and a pot-pourri of organo-aluminium, -boron and -copper catalysts are described, in brief, below. 

Perez-Balderas F, Ortega-Munoz M, Morales-Sanfrutos J et al (2003) Multivalent neogly-coconjugates by regiospecific cycloaddition of alkynes and azides using organic-soluble copper catalysts. Org Lett 5( 11) 1951—1954... 

RC=CKWG) yields 2,4-di-EWG-substituted pyrroles in the presence of copper catalyst but 2,3-di-EWG-substituted pyrroles in the presence of a phosphine catalyst.74 The 3 + 2-cycloaddition of diazoalkanes to (6 )-3-p-tolylsulfinylfuran-2(5//)-one produces diastereoisomeric pyrazolines in almost quantitative yield and with des >98%. (g) The sulfinyl group is responsible for the complete control of the n-facial selectivity in all these reactions.75 The Rh(II)-catalysed intramolecular 1,3-dipolar cycloaddition reaction of diazoamides (57) with alkenyl and heteroaromatic n -bonds yields pen-tacyclic compounds (59), via the ylide (58), in good to excellent yields and in a (g) stereocontrolled manner (Scheme 15).76... 

Ruthenium catalysts were used as alternatives to the usual copper catalysts. Ynamides 102 reacted with various azides 103 in the ruthenium-catalyzed Huisgen [3+2] cycloaddition reaction to yield l-protected-5-amido 1,2,3-triazoles 104 <07T8094>. The formation of 1,5-... 

Cycloaddition of nitrones and pyrazolinones with a copper catalyst and a chiral ligand leads to pyrrolidine derivatives with good enantioselectivity. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

In every case for copper catalyst 31, the absolute stereochemistry of the cycloadducts is accounted for by the intervention of the substrate-catalyst complex depicted in Fig. 23, in which the s-cis configured dienophile is bound to the catalyst in the plane of the ligand in a bidentate fashion. The ferf-butyl group shields the top face and cycloaddition occurs from the exposed si enantioface. Support for this model derives from X-ray structures of aquo complexes of catalysts 31a and 31b which show that the complex possesses a distorted square planar geometry EPR spectroscopy on the binary catalyst-dienophile complex indicates that this geometry carries over from the solid state into solution. Calculations at the PM3 level of theory further favor the indicated reactive assembly [85]. 

It is now usual to promote these cycloadditions by catalysts for example, reaction with A -tosyl-ynamides, using ruthenium or copper catalysts, giving 1-substituted 5- and 4-amino triazoles, respectively the formation of the 1,4-substitution pattern with copper catalysis and 1,5-pattem with ruthenium catalysis seems to be general. The latter metal will also promote addition to internal alkynes. ... 

Another type of multicomponent [2 + 2+1] cycloaddition is achieved with diazo carbonyl compounds in the presence of rhodium or copper catalysts. Reaction with additional carbonyl groups within the substrate gives carbonyl ylides. These, as formal 1,3-dipoles, can undergo [3 + 2] cycloaddition with alkenes or alkynes to form heterocyclic ring systems,7 83... 

A small number of enantiomerically pure Lewis acid catalysts have been investigated in an effort to develop a catalytic asymmetric process. Initial work in this area was carried out by Narasaka and coworkers using the titanium complex derived from diol (8.216) in the cycloaddition of electron-deficient oxazolidinones such as (8.217) with ketene dithioacetal (8.218), alkenyl sulfides and alkynyl sulfides. Cyclic alkenes can be used in this reaction and up to 73% ee has been obtained in the [2- -2] cycloaddition ofthioacetylene (8.220) and derivatives with2-methoxycarbonyl-2-cyclopenten-l-one (8.221) usingthe copper catalyst generated with bis-pyridine (8.222). Furthermore, up to 99% ee has been obtained in the [2-1-2] cycloaddition of norbornene with alkynyl esters using rhodium/Hs-BINAP catalysts. This reaction is not restricted to the use of transition metal-based Lewis... 

The above-described method which employs copper powder to activate 1,3-dipolar cycloaddition reaction of azides and alkynes in ball mill is related to work by Mack et al. [11], Here, copper catalyst was replaced by Cu vial and Cu milling balls as a source of metal catalyst. The efficacy and simplicity of the method is clearly shown by reaction of phenylacetylene and benzylazide in Spex Certiprep 8000M mixer mill (Scheme 5.11). Minute amounts of copper peeled off the balls were sufficient to afford 1,2,3-triazole 38 in excellent yield, without the need for purification of product. The ICP-MS analysis determined very low level of copper metal present in product after isolation (4.61 mg/g of copper in the product). Multicomponent variant of this reaction includes the in situ preparation of... 

At the same time, Cozzi described the immobilization of Box ligands on PEG polymer (polymer 99, Scheme 49), and the corresponding copper catalyst used for the cyclopropanation reaction was also involved in Diels-Alder cycloaddition between cyclopentadiene and/V-acryloyloxazolidinone (Scheme 54) [95]. This reaction was performed with 15 mol% each of Box ligand and Cu(OTf)2 in DMF in order to obtain homogeneous conditions. The reaction occurred in good yield (up to 83%) and excellent diastereoselectivity in favour of the endo stereoisomer (ratio endo/exo >98/2). However, the maximum of enantioselectivity was only 45% contraiy to the non-supported Box equivalent catalyst which led to complete end at 95% ee and 88% yield. 

Chapter 4 concerns the cycloaddition of carbonyl ylides generated from diazo carbonyl compounds and rhodium or copper catalysts. In this framework chemoselective and enantioselective transformations leading to the formation of various heterocycles such as tetrahydrofurans, oxazolidines, mesoionic and bicyclic compoxmds, alkaloids, and other natural products are described. 

In 2014 several reports described the use of inverse-electron-demand Diels-Alder reactions to furnish naphthalene-based compounds from phthalazine-containing ring systems. Employing nonprecious metal complexes, copper(l) and nickel(O) complexes, instead of silver salts to catalyze formal [4+ 2] cycloadditions of 1,2-diazines and siloxyalkynes, Rawal and his group developed an environmentally friendlier and more economical method for preparing siloxy derivatives of naphthalene, anthracene, and phenanthrene (Scheme 16) (140L3236). In addition, the copper catalyst could also be employed for the synthesis of the corresponding quinolines and isoquinolines. This method provided the respective products in... 

The potential for sequential copper-catalyzed processes can also be illustrated in the case of formation of fully substituted 1,2,3-triazoles. In this sequence, the same copper catalyst is promoting two distinct types of catalysis [3+2]-cycloaddition and arylation via C-H activation. Each reaction type tolerates both electron-rich and -poor substrates, as well as steric hindrance, adding noteworthy breadth to this scheme. A 4-component sequence using NaNs, rather than an alkyl azide, is shown below. The diamine DMEDA (W.W -dimethylethylenediamine) is used to stabilize the copper catalyst. 

Other types of heterogeneous copper catalysts have also been developed for the azide-alkyne cycloaddition. Zhang et al. (2013) utilized porous copper(0) to facilitate the three-component reactions in water, and the desired 1,2,3-triazoles could be assembled in good to excellent yields, though long reaction times were usually required (at 55°C for 20-54 h). 

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