This is an author-produced version of the following Elsevier-published article: Belokon, Clegg , Harrington, Young and North, Asymmetric cyanohydrin synthesis using heterobimetallic catalysts obtained from titanium and vanadium complexes of chiral and achiral salen ligands, Tetrahedron, 63 (24), 5287-5299 doi:10.1016/j.tet.2007.03.140 Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. Asymmetric cyanohydrin synthesis using Leave this area blank for abstract info. heterobimetallic catalysts obtained from titaniumO andMe 3SiCN OX OX vanadium complexes of chiral and achiral salen + or 1 (0.1-1 mol%) + ligands R H KCN / Ac2O R CN R CN Yuri N. Belokon’, b William Clegg, a Ross W. X = SiMe3: ratio = 84 : 16 Harrington, a Carl Young a and Michael North a* X = Ac; ratio = 16 : 84 a) School of Natural Sciences, Bedson Building, + - 1 = [(R,R-salen)Ti(µ-O)2V (S,S-salen') EtOSO3 ] Newcastle University, Newcastle upon Tyne, NE1 7RU, UK b) A.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813, Moscow, Vavilov 28, Russian Federation. Tetrahedron 1 TETRAHEDRON Pergamon Asymmetric cyanohydrin synthesis using heterobimetallic catalysts obtained from titanium and vanadium complexes of chiral and achiral salen ligands Yuri N. Belokon’, b William Clegg, a Ross W. Harrington, a Carl Young a and Michael North a* a School of Natural Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK. b A.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813, Moscow, Vavilov 28, Russian Federation Abstract— Titanium(IV)(salen) and vanadium(V)(salen) complexes are both known to form catalysts for asymmetric cyanohydrin synthesis. When a mixture of titanium and vanadium complexes derived from the same or different salen ligands is used for the asymmetric addition of trimethylsilyl cyanide to benzaldehyde, the absolute configuration of the product and level of asymmetric induction can only be explained by in situ formation of a catalytically active heterobimetallic complex, and is not consistent with two monometallic species acting cooperatively. Combined use of complexes containing chiral and achiral salen ligands demonstrates that during the asymmetry inducing step of the mechanism, the aldehyde is coordinated to the vanadium rather than the titanium ion. The titanium complexes also catalyse the asymmetric addition of ethyl cyanoformate to aldehydes, a reaction for which vanadium(V)(salen) complexes are not active. For this reaction, use of a mixture of titanium and vanadium(salen) complexes resulted in a complete loss of catalytic activity, a result which again can only be explained by in situ formation of a heterometallic complex. Both the titanium and vanadium based catalysts also induce the asymmetric addition of potassium cyanide / acetic anhydride to aldehydes. For this reaction, combined use of chiral and achiral complexes indicated that during the asymmetry inducing step of the mechanism, the aldehyde was coordinated to titanium rather than vanadium, a result which contrasts with the observed results when trimethylsilyl cyanide was used as the cyanide source. © 2007 Elsevier Science. All rights reserved 1. Introduction and carbonates, 9 and insoluble, polymeric versions of the catalyst have also been developed and used as catalysts for Cyanohydrins are key synthetic intermediates for the asymmetric cyanohydrin synthesis. 10,11 Closely related synthesis of pharmaceuticals and natural products. As a titanium(salen) complexes have also been used as catalysts result, the development of asymmetric catalysts for the for the enantioselective ring-opening of meso -epoxides, 12 addition of various cyanide sources to carbonyl compounds hetero-Diels-Alder reactions, 13 the asymmetric addition of has increased significantly over the last ten years. 1,2 dialkylzinc reagents to α-ketoesters, 14 the asymmetric Metal(salen) complexes are amongst the most versatile addition of organogallium reagents to aldehydes, 15 and the catalysts for a wide range of reactions, 3 and we have asymmetric oxidation of sulfides. 16 previously reported 4 the development of bimetallic titanium complex 1 as a highly effective catalyst for the asymmetric Subsequently, we have shown that vanadium(V)(salen) addition of trimethylsilyl cyanide to aldehydes 5 and complex 2 is an even more enantioselective catalyst for the ketones 6 at room temperature, and for the asymmetric asymmetric addition of trimethylsilyl cyanide to addition of ethyl cyanoformate 7 and potassium cyanide 8 to aldehydes, 17 and that complex 2 also catalyses the aldehydes at -40 oC. Complex 1 has also been used by other asymmetric addition of potassium cyanide to aldehydes. 8 workers for the asymmetric synthesis of cyanohydrin esters Polymeric, 11 and supported 18 versions of this catalyst have ——— Key words: Asymmetric catalysis; Cyanohydrin; Titanium; Vanadium; Heterometallic complexes * Corresponding author. Tel.: +44-191-222-7128; fax: +44-870-131-3783; e-mail: [email protected]. 2 Tetrahedron been prepared and vanadium(V)(salen) complexes have shown in Figure 1A. However, an alternative mechanism also been used as catalysts for the asymmetric oxidation of involving sequestration of titanium ions by vanadium (for sulfides. 19 A related vanadium(V)(salen) complex was example by formation of a catalytically inactive oligomeric shown to catalyse the asymmetric transfer of hydrogen complex 23 ) leaving only vanadium(salen) complexes to cyanide from acetone cyanohydrin to aldehydes. 20 For both catalyse the reaction through the bimolecular transition complexes 1 and 2, the catalyst derived from ( R,R )- state shown in Figure 1B could not be completely ruled out. cyclohexane diamine always catalyses the formation of the (S)-enantiomer of the cyanohydrin. (salen)M CN OSiMe3 (salen)M CN tBu tBu O (salen)M O H R (salen)M O H R O tBu tBu CN A B N O O O N Figure 1 Ti Ti O N O O N In this manuscript, we report for the first time results on tBu tBu heterobimetallic titanium and vanadium complexes derived from two different salen ligands, one of which is achiral and the other chiral. The catalysis of the addition of various tBu tBu cyanide sources to benzaldehyde using these 1 heterobimetallic systems is investigated, and the results can only be explained by in situ formation of a catalytically active heterobimetallic complex as illustrated in Figure 1A. O EtOSO3 The structure and stereochemistry of the heterobimetallic N N complexes are analysed in detail and can be used to predict V not only the sense and magnitude of asymmetric induction, tBu OO tBu but also the rate of catalysis observed using the complexes. O H H tBu tBu 2. Results and Discussion 2 Mechanistic studies on catalysts 1 and 2 demonstrated that 2.1 Synthesis of achiral salen complexes of titanium and two metal(salen) units were involved in the catalysis and vanadium were consistent with either of the transition state structures shown in Figure 1, where one metal ion acts as a chiral To allow further investigation of the mechanism of Lewis acid, and the other as a chiral cyanide source, with asymmetric cyanohydrin synthesis induced by metal(salen) cyanide then being transferred between the two metals onto complexes, it was decided to combine the use of both 21 enantiomers of catalysts 1 and 2 with the corresponding the coordinated carbonyl compound. Whilst catalyst 2 is 24 more enantioselective than catalyst 1, it accelerates the rate complexes derived from achiral salen ligand 3. Ligand 3 of addition of trimethylsilyl cyanide to aldehydes to a much was converted into the corresponding bimetallic- lower extent. Reactions involving catalyst 1 are typically titanium(salen) complex 4 using the same synthetic route complete in 30 minutes, whereas those involving catalyst 2 developed for the synthesis of catalyst 1 (Scheme 1). require at least 16 hours to reach completion under However, treatment of ligand 3 with vanadyl sulfate in the identical reaction conditions. presence of air, using the methodology developed for the synthesis of catalyst 2,8 did not result in spontaneous We recently reported 22 however, that when the enantiomer oxidation of the vanadium ion and formation of the desired vanadium(V)(salen) complex 5; rather the corresponding of catalyst 1 (( S,S )-1) was mixed with catalyst 2, so as to 25 prepare a solution containing equimolar amounts of vanadium(IV)(salen) complex was isolated and could then be oxidized to the desired vanadium(V) complex 5 by titanium and vanadium ions, the resulting mixture catalysed 19 the formation of the ( S)-enantiomer of mandelonitrile treatment with cumene hydroperoxide. trimethylsilyl ether, a result which was inconsistent with the two catalysts acting independently or with scrambling 2.2 Structural analysis of bimetallic salen complexes of the salen ligand between the two metals. These results could only be explained by catalysis involving at least two In monometallic octahedral complexes, the planar, trans - configuration of a salen ligand is usually energetically metal ions, and indicated that catalysis by two different 26 metal ions was more favourable than catalysis by either preferred (Figure 2). However, in bis -bridged complexes homometallic system. Kinetics experiments indicated that as occurs in complexes 1 and 4, this is not possible as the two bridging oxygens must adopt positions cis to one catalysis by the heterometallic system was slower than 27 22 another. The salen ligand can then adopt either cis -α or catalysis using catalyst 1 alone, which was consistent β 28 with the in situ formation of a heterobimetallic complex as cis - configurations, with the latter being preferred in all Tetrahedron 3 cases known to date. 29,30 The cis -β configuration of a salen A X O O ligand is chiral, and two enantiomeric structures (∆ or Λ) are possible. For bimetallic complexes bearing two N X X O M N N M X N M X different salen ligands, there are thus four possible O N O stereoisomeric configurations ( ∆∆, ΛΛ, ∆Λ and Λ∆ ) of the two salen ligands.