Modern Organocopper Chemistry

278 8 Copper-Mediated Enantioselective Substitution Reactions

The ees obtained in reactions between 21 and di erent Grignard reagents using copper arenethiolate 19b (isolated complex or prepared in situ from 29 and CuX) were improved in all cases when the ferrocenyl system was used. Thus, MeMgI, EtMgI, n-PrMgI, and i-PrMgBr gave ees of 44, 62, 54, and 52% respectively. The enantiomeric excesses obtained using this ligand are the highest so far reported for copper-catalyzed allylic substitution reactions between allylic esters and Grignard reagents.

The necessity of an anionic thiolate ligand was established by performing reactions with ferrocene thioethers 37 as ligands. Here, essentially racemic products were obtained.

Alexakis et al. have also recently studied allylic substitution reactions in the presence of chiral ligands [43]. Their experience with phosphorus-based ligands for copper in conjugate addition reactions [44] prompted them to study these systems in substitution reactions as well. Reactions between cinnamyl chloride and Grignard reagents were chosen as a suitable test system. It turned out to be a challenge to obtain a regioselective reaction with this system in the presence of the ligand triethyl phosphite P(OEt)3. However, it proved possible to obtain a g/a ratio of 97:3 by addition of ethyl magnesium bromide to cinnamyl chloride, CuCN (1 mol%), and P(OEt)3 (2 mol%) in CH2Cl2 at 80 C. By using EtMgCl, with Cu(OTf )2 as catalyst, and carrying out inverse addition of the substrate to a mixture of the catalyst, ligand, and Grignard reagent, the regioselectivity could be switched in favor of the a product (g/a 7:93) [45]. Use of other solvents, such as Et2O, THF, or toluene, produced very low selectivities. Use of cinnamyl acetate (22) as substrate favored the a product.

In total, 29 phosphorus-containing chiral ligands of various structures were screened under the optimized g-selective conditions, but most of them gave little or no chiral induction. The four ligands 38a–d, all derived from ( )-TADDOL, depicted in Fig. 8.4 gave ees in excess of 30% in the reaction between ethyl magnesium bromide and cinnamyl chloride.

Ligand 38a, bearing an ( )-N-methylephedrine substituent, was superior, and gave an ee of 51% and a g/a ratio of 91:9. Further fine-tuning of the reaction conditions gave an improvement to 73% ee and a g/a ratio of 94:6. Optimum enantioselectivity was favored here by a CuCN:ligand ratio of 1:1 and the use of only 1 mol% of each. Slower addition of the Grignard reagent (40 min) also produced improvements. It should be noted, however, that with 2.5 mol% of CuCN, 5 mol% of ligand, and addition of the Grignard reagent over only 20 min, the g/a ratio was 100:0, with an only slightly lower ee (67%).

8.2 Allylic Substitution 279

Fig. 8.4. Ligands 38 employed in allylic substitution reactions between cinnamyl chloride and EtMgBr.

With suitable conditions for the test system established, variations in the structures of the substrate and the Grignard reagent were examined (Scheme 8.22).

Scheme 8.22. Investigation of substrate and Grignard reagent structure.

The e ect of the leaving group was briefly examined, but cinnamyl bromide gave a substantially lower ee (38%). Cinnamyl dimethyl phosphonate, or acetate, gave very poor results. The cyclohexyl-substituted allylic acetate 21, on the other hand, a orded a completely g-selective reaction, but the product turned out to be racemic. Changing the Grignard reagent halide from bromide to either chloride or iodide resulted in very low ees.

The scope of the reaction with cinnamyl chloride was assessed by testing a number of di erent Grignard reagents, including n-alkyl, methyl, aryl, cycloalkyl, isopropyl, and isobutyl derivatives, TMSCH2MgBr, and the sterically crowded neopentylMgBr. Increased steric hindrance, however, resulted in lower ees and none of the tested reagents gave ees as high as EtMgBr had. The bulky neopentyl Grignard reagent gave almost racemic SN20 product. The n-alkyl Grignard reagents n- PrMgBr and n-BuMgBr gave ees of 57 and 52%, respectively. Interestingly, the reaction could also be performed with an aromatic Grignard reagent, but with low ees (21% for 2-MeOaC6H4MgBr).

The reported results show that the reaction is very sensitive to small changes in the reaction conditions, such as temperature. Just a few degrees di erence in the reaction temperature could have a dramatic influence on the outcome of the reaction. No single set of reaction conditions was applicable to all cases, and the depen-

280 8 Copper-Mediated Enantioselective Substitution Reactions

dence of the selectivity on the structure of the Grignard reagent and substrate is hard to interpret.

Organozinc reagents in combination with a catalytic amount of copper catalyst and ligand can be used in place of Grignard reagents. In this case, however, the allylic electrophile has to carry a relatively reactive leaving group, such as a halide; allylic esters do not normally react with organozinc reagents. Knochel et al. discovered that chiral primary amines could function as useful ligands to copper for catalysis of allylic substitution reactions between unsymmetrical allylic chlorides and diorganozinc reagents [41a]. Primary ferrocenyl amines 39 were the most efficient of the ligands studied. These ligands may be obtained easily and with high optical purity from ferrocenyl aryl ketones, by reduction with BH3 SMe2 in the presence of a chiral ligand.

The Ar group in the ligand is very important for the enantioselectivity in the SN20 product. In a screening reaction between cinnamyl chloride and dineopentylzinc, the ligand bearing a 2-naphthyl substituent produced the highest ee (42%). Furthermore, a high ratio of ligand to copper of 10:1 increased the ee to 67% at 50C, while a reduction in the reaction temperature to 90 C resulted in a further increase, to 82% ee. Interestingly, the enantioselectivity showed an almost linear dependence on temperature and only 25% ee was achieved at 25 C.

The influence of the leaving group in the substrate was also investigated, but changes from the Cl in cinnamyl chloride to Br, carbonate, xanthate, or phosphate all resulted in diminished selectivity. The type of organometallic reagent was also very important, and no reaction at all was observed with organozinc reagents of the type RZnX.

To conclude the study, combinations of di erently substituted substrates and diorganozinc reagents were investigated (Scheme 8.23).

Scheme 8.23. Asymmetric allylic substitution catalyzed by 39 (Ar ¼ 2-naphthyl).

The reactions were regioselective in all cases, with g:a ratios of >90:10. The maximum ee, 87%, was obtained by treatment of a substrate containing the elec- tron-withdrawing R1 substituent 4-CF3aC6H4a with dineopentylzinc. Changing the

8.2 Allylic Substitution 281

substrate R1 group to naphthyl, cyclohexyl, or functionalized substituents such as 3-thienyl or silylethers resulted in lower ees being obtained. A change of the R2 group in the diorganozinc reagent from the bulky neopentyl invariably produced lower ees. Bis(trialkylsilylmethyl)zinc gave 42–67% ee. Bis(myrtanyl)zinc reagents of both possible configurations, (þ) and ( ), were also employed, and a orded diastereomeric substitution products with ees of around 40%. The asymmetric induction seems to be highly influenced by steric hindrance and sterically demanding diorganozincs were necessary for obtainment of high ees.

The ferrocenyl amine ligands 39 could be improved further by changing the Ar substituent (Scheme 8.24) [41b].

Scheme 8.24. Improvements of ligand 39.

Steric hindrance in the ligand 39 proved to be very important, and the best results were obtained by introducing sterically demanding substituents on the phenyl ring; 3,5-di-t-butylphenyl, for example, gave a 92% ee in the reaction between cinnamyl chloride and dineopentylzinc. This ligand also gave the best SN20 selectivity, at 98:2. Further optimization, including simultaneous addition of R2Zn and the allylic chloride over 3 h, resulted in an improvement to a 96% ee. Under these conditions a higher reaction temperature ( 30 C) could also be employed without any decrease in ee. With the 2-naphthyl-substituted ligand, the combination of 4-CF3-cinnamyl chloride and dineopentylzinc resulted in the highest ee (98%) of all the substrate combinations studied. This optimized ligand system in all cases produced enantioselectivities higher than those obtained with the 2-naphthyl- substituted ligand employed in the first study. It is also noteworthy that, with this ligand, significant ees (44–65%) could be obtained from the di-n-alkylzinc reagents diethylzinc and dipentylzinc. Further improvements were obtained by the use of a mixed reagent, ethylneopentylzinc, which selectively transferred the ethyl group with an ee of 52%, compared to 44% for Et2Zn.

Functionalized diorganozinc reagents [AcO(CH2)4]2Zn and [EtO2C(CH2)3]2Zn were also employed, giving complete g selectivity in both cases, with ees of 50%.

282 8 Copper-Mediated Enantioselective Substitution Reactions

Woodward et al. have used the binaphthol-derived ligand 40 in asymmetric conjugate addition reactions of dialkylzinc to enones [46]. Compound 40 has also been studied as a ligand in allylic substitutions with diorganozinc reagents [47]. To allow better control over selectivity in g substitution of the allylic electrophiles studied, Woodward et al. investigated the influence of an additional ester substituent in the b-position (Scheme 8.25).

Scheme 8.25. Allylic substitution of 41 in the presence of ligand 40.

The reaction between allylic substrates 41 and Et2Zn, catalyzed by [Cu(MeCN)4]BF4, was indeed very fast, and proceeded with excellent g selectivity. Inclusion of the ligand 40 in the reaction mixture resulted in some enantioselectivity, but rather large quantities of catalyst (10 mol%) and ligand (20 mol%) had to be used to maximize asymmetric induction. The e ect of the leaving group was examined; chloride produced higher ees than bromide did, but the yields obtained were significantly lower. With a mesylate the reaction gave a high yield, but an almost racemic product was obtained, while an allylic formate was unreactive under these conditions. With di erent aryl-substituted allylic chlorides and Et2Zn a maximum of 64% ee was achieved. Changes in temperature between 20 and 40C had a minor influence on the enantioselectivity. The highest ee was obtained with Ar ¼ 4-O2NC6H4, and the reaction seems to be controlled more by electronic factors than by steric ones. For the other g-aryl-substituted substrates 41 investigated, the ees varied between 22% and 36%. The asymmetric version of this reaction is unfortunately characterized by low isolated yields.

It may be concluded from the di erent examples shown here that the enantioselective copper-catalyzed allylic substitution reaction needs further improvement. High enantioselectivities can be obtained if chirality is present in the leaving group of the substrate, but with external chiral ligands, enantioselectivities in excess of 90% ee have only been obtained in one system, limited to the introduction of the sterically hindered neopentyl group.

8.3 Epoxides and Related Substrates 283

Fig. 8.5. Binaphthol-derived phosphoramidite ligands developed by Feringa et al.

8.3

Epoxides and Related Substrates

Ring-opening of oxiranes with organocopper reagents is a well known process in organocopper chemistry, usually proceeding with high selectivity. For vinyl oxiranes, both SN2 and SN20 reaction types are possible and the selectivity can be controlled. Optically active allylic alcohol products can be obtained when starting from nonracemic vinyloxiranes [48].

Asymmetric ring-opening of saturated epoxides by organocuprates has been studied, but only low enantioselectivities (< 15% ee) have so far been obtained [49, 50]. Mu¨ller et al., for example, have reported that the reaction between cyclohexene oxide and MeMgBr, catalyzed by 10% of a chiral Schi base copper complex, gave trans-2-methylcyclohexanol in 50% yield and with 10% ee [50].

The use of vinyl epoxides as substrates in enantioselective copper-catalyzed reactions, on the other hand, has met with more success. An interesting chiral ligand e ect on Cu(OTf )2-catalyzed reactions between cyclic vinyloxiranes and dialkylzinc reagents was noted by Feringa et al. [51]. The 2,20-binaphthyl phosphorus amidite ligands 32 and 43 (Fig. 8.5), which have been successfully used in copper-catalyzed enantioselective conjugate additions to enones [37], allowed kinetic resolution of racemic cyclic vinyloxiranes (Scheme 8.26).

Scheme 8.26. Kinetic resolution of cyclic vinyl oxiranes 44.

The process was SN20-selective in the presence of catalytic amounts of ligands (S)-32 or ðS; R; RÞ-43 and Cu(OTf )2. This is another example of ligand-accelerated catalysis; without the ligand the reaction was much slower and proceeded with low regioselectivity.

When 0.5 equivalents of dialkylzinc were used, ees of more than 90% were obtained, with reasonable isolated yields of up to 38% [52] of the SN20-substituted

284 8 Copper-Mediated Enantioselective Substitution Reactions

products arising from the 1,3-cyclohexadiene monoepoxide 44b and the 1,3-cyclo- heptadiene monoepoxide 44c. The substrate 44a, with a five-membered ring, gave much lower asymmetric induction and the maximum ee was 54%. Ligand 43 was superior to 32 in all cases studied. The yield and ee of the remaining unreacted vinyloxirane was not mentioned.

The vinyloxirane reaction was later extended to methylidene cyclohexene oxide and to related meso derivatives [53]. The e ects of the diastereomeric ligands 42 and 43 (Fig. 8.5), derived from (S)-binaphthol and ðS; SÞor ðR; RÞ-bis-phenylethyl- amine respectively, were investigated. In the case of kinetic resolution of racemic methylidene cyclohexane epoxide 45 with Et2Zn, ligand 42 produced better yields, regioselectivity, and enantioselectivity than 43 (Scheme 8.27).

Scheme 8.27. Reaction between epoxide 45 and Et2Zn, catalyzed by Cu(OTf )2 and ligand 42.

To avoid the inherent limitations of a kinetic resolution process, the reaction was extended to desymmetrization of prochiral meso epoxides. A number of cyclic dimethylidene epoxides were synthesized and subjected to treatment with Et2Zn in the presence of Cu(OTf )2 and ligands 42 or 43. As in the case mentioned above, ligand 42 was superior in terms of selectivity. Cyclohexane derivative 46 gave the ring-opened product with a 97% ee and in a 90% isolated yield, with a g/a ratio of 98:2 (Scheme 8.28). The other substrates investigated produced significantly lower ees of between 66% and 85%.

Scheme 8.28. Reaction between 46 and Et2Zn.

The same authors also studied the alkylation of alkynyl epoxides for formation of optically active a-allenic alcohols under kinetic resolution conditions (Scheme 8.29) [54].

8.3 Epoxides and Related Substrates 285

Scheme 8.29. Reactions of alkynyl epoxides 47 with R2Zn.

With ligand 43 the reaction between 47 and 0.5 equivalent of R2Zn was highly diastereoselective, proceeding in an anti fashion (48/49 b97:3). The regioselectivity depended on the diorganozinc reagent, a low SN20/SN2 ratio of 55:45 being obtained with 47a (R ¼ H) and Me2Zn, but ratios of more than 90:10 with Et2Zn. Ees of up to 38% were obtained for the anti-SN20 product 48 (R0 ¼ Et). The influence of the ligand was investigated for the reaction between 47a and Et2Zn. Compound 42 gave a highly antiand SN20-selective reaction (48/49 > 99:1, (48 þ 49)/ 50 ¼ 97:3), but 48 was almost racemic. The use of TADDOL-derived ligand 51 resulted in a synand SN20-selective reaction to give 49 in 36% ee.

Copper-catalyzed desymmetrization of N-tosylaziridine 52 with Grignard reagents has been reported (Scheme 8.30) [50].

Scheme 8.30. Desymmetrisation of N-tosylaziridine 52.

A number of structurally very di erent copper complexes were employed as catalysts. The copper complex of binaphthol-derived phosphoramidite 32 and the Schi base complex 53 (derived from salicylaldehyde and phenylglycine) gave promising results in a screening reaction between 52 and MeMgBr, and 53 was chosen as the candidate for optimization. The e ect of solvent (THF or Et2O),