Copper , catalysis

For the copper-catalyzed 1,4-addition to 2-cyclohexen-l-one, other alkylmetal reagents have also been employed, achieving high enantioselectivity in some cases [Eqs. (3.2)-(3.4)]. Recently, one example appeared that utilized diphenylzinc as the nucleophile in the presence of phosphoramidite ligand 1 to produce highly enantio-enriched 3-phenylcyclohexanone [Eq. (3.5) 94% ee].  

Nitroalkenes have also been employed in the copper-catalyzed asymmetric 

Ligand 4, which is highly effective for the 1,4-addition of diethylzinc to 2-cyclohexen-l-one, shows relatively wide scope with respect to the p-substituent in the copper-catalyzed asymmetric 1,4-addition of diethylzinc to acyclic nitroalkenes 

Radical vs. ionic mechanisms were described as possible routes to the formation of the iminium ion complex using similar mechanisms to those we have already encountered in this chapter. The radical processes were thought to involve HAT and SET in either order, and the ionic process was thought to involve elimination of water from a nitrogen-amine coordination complex (29). A copper-catalyzed CDC reaction between Al-phenyl tetrahydroisoquinoline (THIQ) and nitromethane was found to proceed in 70% yield when BHT was added, which was taken as evidence for the ionic mechanism. 

In some reactions regular ketones are used as pronucleophiles, raising the question of how, under the conditions of the reaction, the nucleophile is actually formed. In one CUI/O2 CDC reaction it was suggested that the beneficial effect of adding several equivalents of acetic acid to the reaction arose from the acid promoting enolization of the ketone and hence a faster trapping of the intermediate iminium ion.  

The Li catalytic system of CuBr and peroxide behaves differently, with a lesser role for copper in line with the Doyle analysis above. The nucleophile 2-naphthol is found to be reactive in this catalyst system while it is ineffective in the CuCl2-catalyzed reaction. Analysis of the reaction mixture by NMR spectroscopy did not reveal the presence of any iminium ion but rather the formation of appreciable quantities of the perojqr adduct 27c. Formation of this compound was found to be relatively insensitive to the addition of methanesulfonic acid, suggesting a radical pathway for its formation. This conclusion was supported by a slowing of the formation of the peroxy adduct in the presence of BHT, though these experiments are another cautionaiy example of the use of BHT since the additive by no means completely suppressed this reaction pathway. It was postulated that while the formation of the perojqr adduct was radical based (a rate-limiting abstraction of a hydrogen atom was proposed that was supported by a primaiy KIE of 3.4 

The great majority of the more recent literature on metal-free CDC reactions has involved DDQ, so a short detour will be taken to cover mechanistic aspects of this reagent. There has been vigorous debate for decades 

These possibilities were followed by the formulation of others. For example Riichardt and co-workers described the possible mechanistic routes for quinone oxidation of hydroarenes with radical pathways (SET/HAT), ionic pathways (direct hydride transfer) and even pericyclic pathways. The conclusions were that initial H-atom transfer appeared more likely than hydride transfer. 

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When 6-diazopenicillanates are irradiated in the presence of sulfur nucleophiles, predominantly 6/3-substitution products are obtained (77JOC2224). When BFs-EtiO is used to catalyze the reaction with nucleophiles, however, the products are primarily the 6a-isomers (78TL995). The use of rhodium or copper catalysis led primarily to ring-opened thiazepine products, presumably by way of the intermediate (56 Scheme 39) (80CC798). 

Another pathway takes place upon cyclization of hydrazides of benzene carboxylic acids in the presence of CuCl in an inert atmosphere in DMF. However, only the cyclization of hydrazide 76 (R = H) in conditions of copper catalysis makes it possible to isolate compound 77 (yield 20%). Other hydrazides of acetylenylbenzoic acids react to give a complex mixture of products (Scheme 132) (85IZV1367 85MI2). 

In the context of copper catalysis in important synthetic dediazoniations of arene-diazonium ions, Starkey s group (Bolth et al., 1943, Whaley and Starkey, 1946) isolated blue pyridine complexes with the constitution ArCu(C5H5N)3 by adding copper powder to pyridine solutions of ArNjBF4. However, it is unlikely that arylcopper is a relevant intermediate in these reactions (see Sec. 8.6). 

Sulfur dioxide (see above) as well as S02, SO , and SOj have been used as building blocks in three-component sulfone syntheses. It has long been known that aromatic sulfinic acids are easily available from diazonium salts and sulfur dioxide under copper catalysis . Mechanistically, aryl radicals as reactive intermediates add to sulfur dioxide generating arenesulfonyl radicals, which either take up an electron (or hydrogen) yielding a sulfinic acid or add to an olefinic double bond yielding final y -halogenated alkyl aryl sulfones (equation 78). 

Scheme 11.6 gives some examples of the various substitution reactions of aryl diazonium ions. Entries 1 to 6 are examples of reductive dediazonization. Entry 1 is an older procedure that uses hydrogen abstraction from ethanol for reduction. Entry 2 involves reduction by hypophosphorous acid. Entry 3 illustrates use of copper catalysis in conjunction with hypophosphorous acid. Entries 4 and 5 are DMF-mediated reductions, with ferrous catalysis in the latter case. Entry 6 involves reduction by NaBH4. 

It has been found that a number of bidentate ligands greatly expand the scope of copper catalysis. Copper(I) iodide used in conjunction with a chelating diamine is a good catalyst for amidation of aryl bromides. Of several diamines that were examined, rra s-yV,yV -dimethylcyclohexane-l,2-diamine was among the best. These conditions are applicable to aryl bromides and iodides with either ERG or EWG substituents, as well as to relatively hindered halides. The nucleophiles that are reactive under these conditions include acyclic and cyclic amides.149... 

Recently, Pal et al. found that (.S )-prolinol could facilitate the coupling reaction of terminal alkynes with 3-iodoflavone under palladium-copper catalysis in aqueous DMF to give 3-alkynyl substituted flavones of potential biological interest (Eq. 4.17). The coupling of iodobenzene with terminal alkynes at room temperature in water without any cosolvent was completed within 30 minutes, affording the desired product in good yield.36... 

The reaction of crotyl bromide with ethyl diazoacetate once again reveals distinct differences between rhodium and copper catalysis. Whereas with copper catalysts, the products 125 and 126, expected from a [2,3] and a [1,2] rearrangement of an intermediary halonium ylide, are obtained by analogy with the crotyl chloride reaction 152a), the latter product is absent in the rhodium-catalyzed reaction at or below room temperature. Only when the temperature is raised to ca. 40 °C, 126 is found as well, together with a substantial amount of bromoacetate 128. It was assured that only a minor part of 126 arose from [2,3] rearrangement of an ylide derived from 3-bromo-l-butene which is in equilibrium with the isomeric crotyl bromide at 40 °C. 

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. 

Rh2(OAc)4-catalyzed decomposition of 2-diazocyclohexane-l,3-dione 380a or its 5,5-dimethyl derivate 380b in the presence of an aryl iodide leads to an iodonium ylide 381 355). The mild reaction conditions unique to the rhodium catalyst are essential to the successful isolation of the ylide which rearranges to 382 under the more forcing conditions required upon copper catalysis (copper bronze, Cu(acac)2, CuCl2) 355). 

Copper, and occasionally silver, have been used as catalysts for hydroformylation of a-olefins. Phosphite complexes of copper(I) chloride have been claimed as catalysts (126). Phthalocyanine complexes of Group IB metals have been stated to show a low degree of catalytic activity (127). One of the more interesting examples of copper catalysis was disclosed by McClure (128). Copper powder, with a controlled amount of water (0.2-4.0 moles H20/mole Cu), gave a slow conversion of pro-... 

Mannich-type chemistry and cross-dehydrogenative couplings between t/i3-C-H and t/i-G-H bonds can be mediated by copper catalysis (Equations (43) and (44)).49,49a It is to be noted that the nitrogen atom mediates the... 

The conventional wisdom that one-electron oxidants react with thiols to yield disulfides is apparently derived from reactions in which trace copper catalysis dominated the chemistry. 

Evans et al. (219, 220) examined the use of electron-poor heterodienes as partners in cycloadditions with electron-rich alkenes under copper catalysis. In particular, a,p-unsaturated acylphosphonates and keto-esters afford hetero-Diels-Alder adducts in high selectivities when treated with enol ethers in the presence of catalysts 269c and 269d. 

Although the resulting vinylallenes 48 were usually obtained as mixtures of the E and Z isomers, complete stereoselection with regard to the vinylic double bond was achieved in some cases. In addition to enyne acetates, the corresponding oxiranes (e.g. 49) also participate in the 1,5-substitution (Scheme 2.18) and are transformed into synthetically interesting hydroxy-substituted vinylallenes (e.g. 50) [42], Moreover, these transformations can also be conducted under copper catalysis by simultaneous addition of the organolithium compound and the substrate to catalytic amounts of the cuprate (see Section 3.2.3). 

For reviews of copper catalysis involving chiral heteroatomcuprates prepared from anionic ligands see (a)... 

For reviews on copper catalysis involving neutral chiral heteroatom ligands see (a) A. Alexakis, Chimia,... 

The conjugate addition of organometallic reagents R M to an electron-deficient alkene under, for instance, copper catalysis conditions results in a stabilized car-banion that, upon protonation, affords the chiral yS-substituted product (Scheme 7.1, path a). Quenching of the anionic intermediate with an electrophile creates a disubstituted product with two new stereocenters (Scheme 1, path b). With a pro-chiral electrophile, such as an aldehyde, three new stereocenters can be formed in a tandem 1,4-addition-aldol process (Scheme 1, path c). 

Figure 3.1. Chiral ligands that exhibit >95% ee in the reaction between 2-cyclohexen-l-one and diethylzinc under copper catalysis.

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