Copper Diels-Alder reactions

The rate of the uncatalysed reaction in all four solvents is rather slow. (The half-life at [2.5] = 1.00 mM is at least 28 hours). However, upon complexation of Cu ion to 2.4a-g the rate of the Diels-Alder reaction between these compounds and 2.5 increases dramatically. Figure 2.2 shows the apparent rate of the Diels-Alder reaction of 2.4a with 2.5 in water as a lunction of the concentration of copper(II)nitrate. At higher catalyst concentrations the rate of the reaction clearly levels off, most likely due to complete binding of the dienophile to the catalyst. Note that in the kinetic experiments... 

Figure 2.2. Second-order rate constant for the Diels-Alder reaction of 2.4a with 2.5 in aqueous solution as a function of the concentrations of copper(II)ni trate.

In the previous section efficient catalysis of the Diels-Alder reaction by copper(II)nitrate was encountered. Likewise, other bivalent metal ions that share the same row in the periodic system show catalytic activity. The effects of cobalt(II)nitrate, nickel(II)nitrate, copper(II)nitrate and zinc(ll)nitrate... 

Copper is clearly the most selective metal-ion catalyst. Interestingly, proton catalysis also leads to high selectivities. This is a strong indication that selectivity in this catalysed Diels-Alder reaction does not result from steric interactions. 

Evans and co-workers investigated the effect of a number of -symmetric bis(oxazoline) ligands on the copper(II)-catalysed Diels-Alder reaction of an N-acyloxazolidinone with cyclopentadiene. Enantiomeric excesses of up to 99% have been reported (Scheme 3.4). Evans et al." suggested transition state assembly 3.7, with a square planar coordination environment around the central copper ion. In this scheme the dienophile should be coordinated predominantly in an cisoid fashion in... 

Interestingly, the rate constants for Diels-Alder reaction of the ternary complexes with 3.9 are remarkably similar. Only with 2,2 -bipyridine and 1,10-phenanthroline as ligands, a significant change in reactivity is observed. It might well be that the inability of these complexes to adopt a planar geometry hampers the interaction between the copper ion and the dienophile, resulting in a decrease of the rate of the catalysed Diels-Alder reaction. 

In contrast, investigation of the effect of ligands on the endo-exo selectivity of the Diels-Alder reaction of 3.8c with 3.9 demonstrated that this selectivity is not significantly influenced by the presence of ligands. The effects of ethylenediamine, 2,2 -bipyridine, 1,10-phenanthroline, glycine, L-tryptophan and L-abrine have been studied. The endo-exo ratio observed for the copper(II)-catalysed reaction in the presence of these ligands never deviated more than 2% from the endo-exo ratio of 93-7 obtained for catalysis by copper aquo ion. 

Likewise, the influence of the ligand catalyst ratio has been investigated. Increase of this ratio up to 1.75 1 resulted in a slight improvement of the enantioselectivity of the copper(L-tryptophan)-catalysed Diels-Alder reaction. Interestingly, reducing the ligand catalyst ratio from 1 1 to 0.5 1 resulted in a drop of the enantiomeric excess from 25 to 18 % instead of the expected 12.5 %. Hence, as anticipated, ligand accelerated catalysis is operative. 

In summary, when using a ligand catalyst ratio of 1.75 1 at pH 5-6 the enantioselectivity of the Diels-Alder reaction between 3.8c and 3.9 is dictated by the activated complexes involving ligand, copper(ir) ion, dienophile and diene. Considering that four different products are formed in this reaction (see Scheme 3.5), at least four different activated complexes are involved However, each of these complexes hus two degrees of freedom that determine the stereochemical outcome of the... 

Table 3.4. Enantiomeric excess and reaction times of the copper(L-abrine)-catalysed Diels-Alder reaction of3.8cwith3.9in different solvents at 0 C.

As anticipated from the complexation experiments, reaction of 4.42 with cyclopentadiene in the presence of copper(II)nitrate or ytterbium triflate was extremely slow and comparable to the rate of the reaction in the absence of Lewis-acid catalyst. Apparently, Lewis-acid catalysis of Diels-Alder reactions of p-amino ketone dienophiles is not practicable. 

Note that for 4.42, in which no intramolecular base catalysis is possible, the elimination side reaction is not observed. This result supports the mechanism suggested in Scheme 4.13. Moreover, at pH 2, where both amine groups of 4.44 are protonated, UV-vis measurements indicate that the elimination reaction is significantly retarded as compared to neutral conditions, where protonation is less extensive. Interestingy, addition of copper(II)nitrate also suppresses the elimination reaction to a significant extent. Unfortunately, elimination is still faster than the Diels-Alder reaction on the internal double bond of 4.44. 

Fortunately, in the presence of excess copper(II)nitrate, the elimination reaction is an order of magnitude slower than the desired Diels-Alder reaction with cyclopentadiene, so that upon addition of an excess of cyclopentadiene and copper(II)nitrate, 4.51 is converted smoothly into copper complex 4.53. Removal of the copper ions by treatment with an aqueous EDTA solution afforded in 71% yield crude Diels-Alder adduct 4.54. Catalysis of the Diels-Alder reaction by nickel(II)nitrate is also... 

In this section the catalytic efficiency of Co(DS)2, Ni(DS)2, Cu(DS)2 andZn(DS)2 micelles as well as the effect of CTAB and C12E7 on the copper-ion catalysed Diels-Alder reaction between 5.1 and 5.2 is described... 

Table 5.5. Influence of micelles of Cu(DS)2, CTAB and C12E7 on the apparent second-order rate constants (M s" ) for the copper(II) catalysed Diels-Alder reaction of 5.1c, 5.If and 5.1 g with 5.2 at 25 C .

Table 5.6. Hammett -values for the copper(II)-catalysed Diels-Alder reaction of 5.1a-e with 5.2 in different media.

Also the arene-arene interactions, as encountered in Chapter 3, are partly due to hydrophobic effects, which can be ranked among enforced hydrophobic interactions. Simultaneous coordination of an aromatic oc amino acid ligand and the dienophile to the central copper(II) ion offers the possibility of a reduction of the number of water molecules involved in hydrophobic hydration, leading to a strengthening of the arene-arene interaction. Hence, hydrophobic effects can have a beneficial influence on the enantioselectivity of organic reactions. This effect is anticipated to extend well beyond the Diels-Alder reaction. 

In contrast to SDS, CTAB and C12E7, CufDSjz micelles catalyse the Diels-Alder reaction between 1 and 2 with enzyme-like efficiency, leading to rate enhancements up to 1.8-10 compared to the reaction in acetonitrile. This results primarily from the essentially complete complexation off to the copper ions at the micellar surface. Comparison of the partition coefficients of 2 over the water phase and the micellar pseudophase, as derived from kinetic analysis using the pseudophase model, reveals a higher affinity of 2 for Cu(DS)2 than for SDS and CTAB. The inhibitory effect resulting from spatial separation of la-g and 2 is likely to be at least less pronoimced for Cu(DS)2 than for the other surfactants. 

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). 

With few exceptions chiral Lewis acids are usually moisture-sensitive and require anhydrous conditions, but bench-stable aquo complexes such as [Cu(S,S)-t-Bu-box)(H20)2](SbF6)2 were found to promote the Diels-Alder reaction as effectively as the anhydrous copper reagent. 

A great advantage of catalyst 24b compared with other chiral Lewis acids is that it tolerates the presence of ester, amine, and thioether functionalities. Dienes substituted at the 1-position by alkyl, aryl, oxygen, nitrogen, or sulfur all participate effectively in the present asymmetric Diels-Alder reaction, giving adducts in over 90% ee. The reaction of l-acetoxy-3-methylbutadiene and acryloyloxazolidinone catalyzed by copper reagent 24b, affords the cycloadduct in 98% ee. The first total synthesis of ewt-J -tetrahydrocannabinol was achieved using the functionalized cycloadduct obtained [23, 33e] (Scheme 1.39). 

Although furan is usually a poor diene in the Diels-Alder reaction, the chiral copper reagent 24b promotes its asymmetric addition to acryloyloxazolidinone to afford the 7-oxabicyclo[2.2.1]hept-2-ene derivative in high optical purity (Scheme 1.40). Because a retro-Diels-Alder reaction occurs above -20 °C, the reaction must be performed at low temperature (-78 °C) to obtain a high optical yield. The bicy-... 

The chiral copper reagent 24 is an effective catalyst not only for intermolecular, hut also for intramolecular Diels-Alder reactions, as shown in the following schemes (Scheme 1.41, 1,42, 1.43). Synthetically useful octalin and decalin skeletons were synthesized in high enantio- and diastereoselectivity. The synthetic utility of this intramolecular Diels-Alder reaction has been demonstrated hy a short total synthesis of isopulo upone [23, 33d]. 

Since Evans s initial report, several chiral Lewis acids with copper as the central metal have been reported. Davies et al. and Ghosh et al. independently developed a bis(oxazoline) ligand prepared from aminoindanol, and applied the copper complex of this ligand to the asymmetric Diels-Alder reaction. Davies varied the link between the two oxazolines and found that cyclopropyl is the best connector (see catalyst 26), giving the cycloadduct of acryloyloxazolidinone and cyclopentadiene in high optical purity (98.4% ee) [35] (Scheme 1.45). Ghosh et al., on the other hand, obtained the same cycloadduct in 99% ee by the use of unsubstituted ligand (see catalyst 27) [36] (Scheme 1.46, Table 1.19). 

The cationic aqua complexes prepared from traws-chelating tridentate ligand, R,R-DBFOX/Ph, and various transition metal(II) perchlorates induce absolute enantio-selectivity in the Diels-Alder reactions of cyclopentadiene with 3-alkenoyl-2-oxazoli-dinone dienophiles. Unlike other bisoxazoline type complex catalysts [38, 43-54], the J ,J -DBFOX/Ph complex of Ni(C104)2-6H20, which has an octahedral structure with three aqua ligands, is isolable and can be stored in air for months without loss of catalytic activity. Iron(II), cobalt(II), copper(II), and zinc(II) complexes are similarly active. 

Keywords hefero-Diels-Alder reaction, chiral bis(oxazoline) copper(ll) complexes... 

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]. 

Tang synthesized pseudo-Cs-symmetric tris(oxazofines) in two steps from the corresponding triester and the amino alcohol [78]. They tested them as copper ligand for enantioselective Diels-Alder reaction [79]. 

Bis(oxazohnes) figands have been so widely used for the Diels-Alder reaction between N-2-alkenoyl-l,3-oxazolidine-2-one and cyclopentadiene that Lipkowitz and Pradhan developed a QSAR (quantitative structure-activity relationship) using Comparative Molecular Field Analysis (CoMFA) for a set of 23 copper-catalysts containing mainly bis(oxazoline) figands. The generated... 

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

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