Titanium ketones phenylation

In 2003, both Walsh and Yus reported independently on a titanium-mediated phenyl transfer to alkyl-aryl ketones 23 (Scheme 8.8) [22]. The role of the titanium alkoxide was not only to form the active chiral catalytic species, but also to sequester the tertiary alkoxide generated during the catalytic cycle. Yus has discussed the possibility of using either arylboronic acids or Ph3B as precursors for the aryl transfer, and in certain cases ee-values greater than 99% were observed [23]. It is worth highlighting at this point that Walsh also used a similar protocol for the aryl transfer to a,P-unsaturated ketones to produce optically enriched tertiary alcohols [24]. 

Titanium(IV) is a powerful but selective Lewis acid which can promote the coupling of allylsilanes with carbonyl compounds and derivatives In the presence of titanium tetrachlonde, benzalacetone reacts with allyltnmethylsilane by 1,4-addition to give 4-PHENYL-6-HEPTEN-2-ONE. Similarly, the enol silyl ether of cyclopentanone is coupled with f-pentyl chloride using titanium tetrachlonde to give 2-(tert-PENTYL)CYCLOPENTANONE, an example of a-tert-alkylation of ketones. 

A solution of 0.11 mol of 1.5M butyllithium in hexane is added to 30 mL of THF under a layer of argon or nitrogen at —78 C, followed by 0.10 mol of (4S,5/ )-1-allyl-3,4-dimcthyl-5-phenyl-2-imidazolidinone in 75 mL of THF. After 25 min, a solution of 0.11 mol of chlorotris(diethylamino)titanium in 30 mL of THF is introduced. The mixture is stirred at — 20 °C for 45 min, then 0.11 mol of the aldehyde or ketone in 10 mL of THF is added. After 2 h. 20 mL of water and 200 mL of diethyl ether are added. The ethereal solution is separated, washed with 20 mL of 10% aq NaHS03 followed by 20 mL of water, dried over Na2S04 and concentrated, whereupon the product crystallizes. Diastereomerically pure samples are prepared by recrystallization from hexane or hexane/ethyl acetate. 

Other unsaturated ketones to which allene 2 undergoes cycloaddition include cyclopent-2-enone, l-phenyl-but-2-enone, l,4-diphenyIbut-2-enone, l-phenyloct-2-enone and acrylonitrile in yields ranging from 60 to 92%. The use of a chiral titanium(IV) catalyst gives chiral methylenecyclobutanes 5 with optical yields of at least 94%.2... 

Phenylthioalkylation of silyl enol ethers. Silyl enol ethers of ketones, aldehydes, esters, and lactones can be alkylated regiospecifically by a -chloroalkyl phenyl sulfides in fhe presence of a Lewis acid. Zinc bromide and titanium(IV) chloride are the most effective catalysts. The former is more satisfactory for enol ethers derived from esters and lactongs. ZnBr2 and TiCL are about equally satisfactory for enol ethers of ketones. The combination of TiCL and Ti(0-f-Pr)4 is more satisfactory for enol ethers of aldehydes. Since the products can be desulfurized by Raney nickel, this reaction also provides a method for alkylation of carbonyl compounds. Of more interest, sulfoxide elimination provides a useful route to a,B-unsaturated carbonyl compounds. 

Thus, when cyclohexyl selenides 1, prepared from the corresponding 4-sub-stituted cyclohexanone via the selenoketals, were oxidized with various Davis and Sharpless oxidants, the chiral alkyl aryl 4-substituted cyclohexylidenemethyl ketones were obtained in excellent chemical yields with high enantiomeric excesses. Typical results are summarized in Table 4. In this asymmetric induction, of the substrate and the chiral oxidant employed were revealed to show a remarkable effect upon the enantioselectivity of the product. The use of a methyl moiety as instead of a phenyl moiety gave a higher ee value, probably due to the steric difference between the two groups bonded to the selenium atom of the substrate. The results indicate that the titanium complex of the Sharpless oxidant may promote the racemization of the chiral selenoxide intermediate by acting as a Lewis acid catalyst, whereas the racemization in the case of the Davis oxidant, which is aprotic in nature, is slow. 

Reductive cyclization of 2-(t>/X t>-nitro)phenyl imidazoles 817, 819 (Scheme 203) in the presence of an orthoester or a ketone is promoted by a low-valent titanium reagent TiCU-Zn to afford imidazo[l,2-f]quinazolines 818 and 5,6-dihydroimidazo[l,2-r ]quinazolines 820 <2005JHC173>. Notably, halogens are not reduced under these conditions. 

The direct selenoacetalization of carbonyl compounds by selenols is by far the shortest and most convenient route to selenoacetals. The reaction is usually carried out at 20 C with zinc chloride (0.5 equiv. versus the carbonyl con x>und) and delivers rapidly (<3 h) and in reasonably good yields methyl and phenyl selenoacetals derived from aliphatic aldehydes and ketones and cyclic ketones (Scheme 69). Selenoacetalization is more difficult to achieve with hindered ketones, such as adamantanone and diisopropyl ketone, and with hindered aromatic carbtmyl compounds. In these cases the reaction is best achieved with titanium tetrachloride instead of zinc chloride and is often limited to the methylseleno derivatives (Scheme 78). Tris(methylseleno)borane offers the advantage of not requiring an acid catalyst and is particularly useful for the selenoacetalization of acid labQe aldehydes such as citronellal (Scheme 70, e). 

Further evidence for the proposed mechanism in which both the alcohol and ketone are co-ordinated to the same Lewis-acid metal site came from the liquid-phase reaction of prochiral phenylacetone with (5)-2-butanol [33]. Both the aluminum- and titanium-containing zeolite Beta catalysts gave the corresponding alcohol in an enantiomeric excess (e. e.) of 34%. The positive rotation of the reaction mixture after removal of the excess alcohol proved the preferred formation of the (5)-(+)-l-phenyl-2-propanol enantiomer. The formation of the (S) enantiomer can be explained by the preferential orientation of the bulky benzyl group of phenylacetone relative to the spatially smaller methyl group of (5)-2-butanol in the transition state (Scheme 6). 

Carbonyl compounds include isobut3raldehyde, phenyl isopropyl ketone, glyoxylic acid and pyruvic acid. Diaryl ketones do not react. Modifications of the method consist in the use of a borohydride exchange-resin, of sodium triacetoxyborohydride NaBH(OAc)3 or in treating a mixture of a ketone and an amine with an equivalent of titanium(IV) chloride and Hiinig s base (ethyldiisopropylamine) in dichloromethane, followed by a methanolic solution of sodium cyanoborohydride. The borane-pridine complex and hydrogen telluride are excellent replacanents for sodium cyanoborohydride. 

Scheme 8.8 Zinc/titanium-mediated enantioselective phenylation of ketones 23.

Scheme 7.49 Highly enantioselective catalytic phenylation of ketones with a constrained geometry titanium catalyst, as described by Walsh and coworkers [79].

Reactions of Enolates and Enolate Equivalents.—Several papers have appeared on the use of enolates released from silyl enol ethers by Lewis acids. Fleming reports the regiospecific alkylation of either the thermodynamic or the kinetic silyl enol ethers with chloromethyl phenyl sulphide in the presence of titanium(iv) chloride. Oxidative or reductive removal of the sulphur gives a-methylene- or a-methyl-ketones respectively (Scheme 69). ... 

Tanabe and coworkers reported the first instances of additions of titanium enolates to ketones [8]. They reported moderate to excellent yields for several reactions. When the two substituents on the ketone were sufficiently sterically differentiated, good to excellent syn diastereoselectivity was observed. Representative examples of these crossed-aldol reactions are shown in Table 2.1. The initial method involved a catalytic (5 mol%) amount of trimethylsilyl trifiate in the reaction mixture it was suggested this generates a trichlorotitanium trifiate species in situ which is more effective at enoli-zation. This theory was, however, called into question by reports of additions of enolates to ketones with trimethylsilyl chloride as catalyst, which also provides moderate to good yields [9]. Additions of enolates of phenyl esters or phenyl thioesters to ketones were also shown to proceed in good yield and with syn diastereoselectivity in the absence of silyl additive [10]. 

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