Titanium cyanates

Salen ligands have also been used in the titanium-catalyzed trimethylsilyl-cyanation of benzaldehyde. The complexes were immobilized by substitution of a chloride with a surface silanol from the support. In the first study on this reaction [38], the most efficient ligand was the non-symmetrical salen Im (Fig. 11) (94% ee), whereas the selectivity obtained with the symmetrical ligand la was significantly lower (72% ee). In a recent paper, the immobilization of different titanium species, including monomeric and dimeric systems with... 

Complexation of an amino acid derivative with a transition metal to provide a cyanation catalyst has been the subject of investigation for some years. It has been shown that the complex formed on reaction of titanium(IV) ethoxide with the imine (40) produces a catalyst which adds the elements of HCN to a variety of aldehydes to furnish the ( R)-cyanohydrins with high enantioselectivity[117]. Other imines of this general type provide the enantiomeric cyanohydrins from the same range of substrates11171. 

Cyanation of aldehydes and ketones is an important chemical process for C C bond formation." " Trimethylsilyl cyanide and/or HCN are commonly used as cyanide sources. The intrinsic toxicity and instability of these reagents are problematic in their applications. Acetyl cyanide and cyanoformates were used as cyanide sources in the enantioselective cyanation of aldehydes catalyzed by a chiral Ti complex and Lewis base (Scheme 5.31)." The Lewis base was necessary for the good yields and selectivities of these reactions. The desired products were obtained in the presence of 10mol% triethyl amine and 5mol% chiral titanium catalyst (Figure 5.14). Various aliphatic and aromatic aldehydes could be used in these reactions. 

Very few methods developed recently are applicable to the cyanation of not only electron-rich but also electron-deficient aromatic, as well as aliphatic aldehydes. Titanium(IV)-derived complex 1 (Fig. 1), reported by Uang, catalyzes the hydro cyanation of aromatic, a, 3-unsaturated, and aliphatic aldehydes with high enantioselectivity (>88% ee for all substrates reported) [15]. Similarly, Ti(IV)-catalyst 2 developed by Choi has proved to be highly enantioselec-tive for the cyanation of various classes of aldehydes (>90% ee for most substrates) [16]. Belokon and co-workers reported two chiral salen-based systems (salen)VO catalyst 3a and [(salen)TiO]2 3b, both of which provided moderate levels of enantioselection when applied to the asymmetric cyanation of diverse... 

Narasaka has reported that TADDOL-Ti dichloride catalyzes the asymmetric addition of trimethylsilylcyanide to aromatic and aliphatic aldehydes (Sch. 63) [148]. The reactions proceed only in the presence of MS 4A. In reactions with aliphatic aldehydes a chiral cyanotitanium species obtained by mixing of the TADDOL-Ti dichloride and trimethylsilylcyanide before addition of the aldehydes acts as a better chiral cyanating agent and affords higher enantiomeric excesses. Chiral titanium complexes obtained from an alcohol ligand and salicylaldehyde-type Schiff bases and a salen ligand have been reported to catalyze the asymmetric addition of hydrogen cyanide or... 

In catalytic processes with enzymes such as D-oxynitrilase and (R) xynitrilase (mandelonitrilase) or synthetic peptides such as cyclo[(5)-phenylalanyl-(5)-histidyl], or in reaction with TMS-CN pro-mot by chiral titanium(IV) reagents or with lanthanide trichlorides, hydrogen cyanide adds to numerous aldehydes to form optically active cyanohydrins. The optically active Lewis acids (8) can also be used as a catalyst. Cyanation of chiral cyclic acetals with TMS-CN in the presence of titanium(IV) chloride gives cyanohydrin ethers, which on hydrolysis lead to optically active cyanohydrins. An optically active cyanohyrMn can also be prepared from racemic RR C(OH)CN by complexation with bru-... 

Cyanation of acetals was achieved either by means of i-butyl isocyanide or 3-trimethylsilylethyl isocyanide in the presence of titanium(IV) chloride (equation 13) or by TMS-CN in the presence of electrogenerated acid. ... 

Since the addition of HCN to carbonyl compounds proceeds in the presence of a catalytic base, asynunetric cyanation should also be possible by using metal alkoxides such as boron, aluminum, titanium, zirconium, and lanthanoids through modification with an optically active substituent or ligand. Mori and Inoue reported that the titanium complex of an acyclic dipeptide composed of... 

Cyano(trimehyl)silane (TMSCN) serves as a cyanating agent for carbonyl groups in the presence of a catalytic or stoichiometric amount of a Lewis acid such as boron trifluoride, titanium(IV) chloride, tin(IV) chloride, etc. Thereby, a wide variety of chiral ligands was designed and used for asymmetric cyanation reactions. Among them, titanium complexes have mostly been employed as the catalysts. 

Catalytic asymmetric cyanation using 20 mol % of the complex of Ti(Oz-Pr)4 with diisoporpyl tartrate (10 Fig. 1) was reported by Oguni [42,43]. The mixture of Ti(Oi-Pr)4 and 10 (Fig. l)did not exhibit high enantioselectivity. Moreover, the selectivity and the reactivity were still low when the formed isopropyl alcho-hol was removed under reduced pressure using the freeze-dry method. High reactivity and an enantioselectivity of up to 90% were observed when the isopropyl alcohol was again added to the freeze-dried titanium complex. 

Cyanation reactions. New catalysts for converting carbonyl compounds to 0-tri-methylsilyl cyanohydrins by MesSiCN include Cp2FePFg and NbFs. Derivatization of ketones can use the titanium complex of or (Ph3PBn)Cl. ... 

Titanium(IV) chloride-amines. I Reductive cyanation.. Aroi... 

Avecia, a former part of the Zeneca Group, developed a range of cheap and highly active titanium- or vanadium-based salen catalysts called CACHy catalysts (Scheme 23). They are based on Jacobsen s salen technology, but they are much more reactive and can, for example, be used in concentrations as low as 0.1 mol% in the cyanation of aryl aldehydes. The catalysts show similar reactivity with alkyl aldehydes and ketones and are applicable to the synthesis of the commercially important mandelic acid derivatives. 

Another strategy to immobilise salen-titanium complexes was reported with silica MCM-41 inorganic support. The obtained catalysts gave high enantiomeric excesses in the cyanation of benzaldehyde, but were poorly... 

Khan and coworkers prepared the ligand 23, which led to complex 24 bearing four titanium atoms after the addition of titanium tetraisopropoxide and water (Scheme 7.17). The cyanation of aldehydes with KCN/AC2O works similarly to complex 19, giving acylated cyanohydrins in nearly quantitative yields and 85-95% enantiomeric excesses. Importantly, complex 24 precipitated after addition of hexane to the reaction mixture, and the filtrated catalyst was reused without affecting the enantiomeric excess (the yield decreases to 88% after 4 runs). 

Self-supported chiral titanium clusters were prepared by mixing the ligand and titanium alkoxide in anhydrous toluene, followed by addition of a small amount of water (Scheme 7.22). In some cases, the cluster was completely insoluble in the reaction medium, especially in the case of 30. The cyanation works well with this heterogeneous catalyst, which was reused many times with no significant loss of activity. Additional experiments revealed that no appreciable amount of chiral catalyst had leached into the solution and the enantioselectivity came only from the solid catalyst. 

Tridentate chiral Schiff bases derived from (- -)-Q -pinene (123) catalyse enantioselective addition of diethylzinc to aryl aldehydes. Steric, aryl stacking, and electronic effects are significant in the transition state, the latter being probed by a Hammett plot of ee versus for a series of benzaldehydes. Complexes of the Schiff base (123) with titanium(IV) catalyse enantioselective cyanation. ... 

Strecker reaction A robust heterogeneous self-supported chiral titanium cluster (SCTC) catalyst applied both in batch and continuous mode [44] enabled imine cyanation as well as a three-component Strecker reaction using the corresponding aldehydes and amines under continuous flow conditions in a PBR giving aminonitriles enantiomeric excess values of up to 98%. 

Seayad, A.M., Ramalingam, B., Chai, C.LL, Li, C., Garland, M.V., and Yoshinaga, K. (2012) Self-supported chiral titanium cluster (SCTC) as a robust catalyst for the asymmetric cyanation of imines under batch and continuous flow at room temperature. Chem. Eur. J., 18, 5693-5700. doi 10.1002/chem.201200528... 

Optically active cyanohydrins can be easily transformed to P-hydroxy amines, a-hydroxy and a-amino carboxylic acids, which represent versatile intermediates for the synthesis of biologically important compounds, including insecticides and medicines [189, 190]. Asymmetric cyanation of carbonyl compounds catalyzed by chiral metal complexes, particularly titanium compounds, has provided one of the most convenient protocols to the access of these type of compounds. The first example of catalytic asymmetric cyanation of aliphatic aldehydes was realized in Reetz s group using BINOL-Ti complex as the catalyst to give the cyanohydrins in up to 82% ee [104] (Scheme 14.85). 

A multicomponent bifunctional catalytic system based on a titanium complex was also used for the efficient enantioselective cyanation of aldehydes with ethyl cyanoformate [221]. The catalyst was readily prepared by the reaction of Ti(O Pr)4 with (S)-6,6 -Br2BINOL in combination with cinchonine and (lR,2S)-(—)-N-methylephedrine. As shown in Scheme 14.91, the optimized catalyst combination (10 mol%) promotes the reaction smoothly to afford the desired cyanohydrins ethyl carbonates in moderate to excellent isolated yields (up to 95%) with high enantioselectivities (up to 94% ee). Although the mechanistic aspects... 

Other works by the same group on the cyanation of a-ketoesters with acetyl cyanide revealed that, when using a ketone as substrate, a chiral base such as cinchonidine became responsible for enantioselection instead of the chiral titanium(iv) salen complex (Scheme 7.18), leading to the corresponding tertiary cyanohydrins in good enantioselectivities of up to 82% ee. ... 

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