Titanium Lewis acid

Scheme 11.45 shows a proposal for the transition state involved in a related Lewis acid catalyzed cycloaddition where a disubstituted dipolarophile is used and endo/exo issues are examined. By coordination of the bulky titanium Lewis acid catalyst, the a-carbon of the acceptor becomes sterically more hindered, disfavoring exo-approach, which involves a serious steric interaction of the benzylidene phenyl moiety with the ligands on the titanium ion. Accordingly, the endo-cycloadduct is the only product observed. 

The Michael addition of methyl a-acetamidoacrylate (196) with pyrrole (1) under silica-supported Lewis acid (Si(M) Si(Zn), Si(Al) and Si(Ti)) assisted by microwave irradiation (MW) afforded the alanine derivatives 395 and 396 dependent on the reaction conditions (Scheme 81) [153]. Both MW and thermal activation for pyrrole gave only Michael product 396, whereas alanine derivatives 395, which are the a-Michael addition product, and 396 were observed with A1 and Ti-catalyst. This behavior shows that aluminium and titanium Lewis acids can form a new acceptor in an irreversible way. The Si(M) or p-TsOH catalyzed reactions of N-benzylpyrrolc 397 with the acrylate 196 under MW gave the product 398 as sole product. The reaction yield has been increased by using a catalytic amount of p-TsOH (Scheme 82). 

Chiral titanium Lewis acids belong today to a very promising class of catalysts. In contrast to boron(Ill), titanium(IV) has the advantageous ability to expand its coordination sphere from tet-... 

Another important research direction is the mimieking of enzymes and the construction of selective catalysts. For these purposes, the polymer is imprinted with the desired reaetion-product or better, a molecule which resembles the transition state of the reaction adducts. If the educts bind specifically to the recognition site, they become confined into these micro-reactors and are supposed to react faster and more defined than outside the cavities [445]. Examples for reactions in the presence of such synthetic enzymes can be found in [452,453,454,455,456,457] (cf Figure 40c). First positive results have been reported, e.g. an synthetic esterase , increasing the rate of alkaline hydrolysis of substituted phenyl-(2-(4-carboxy-phenyl)-acetic esters for 80 times [488] and Diels-Alder catalysis fiuic-tional holes containing titanium lewis-acids [489]... 

Chelation cf prochiral dienophiles by chiral boron, aluminum and titanium Lewis acids 4.13,33 Tartrate-derived chiral acyloxyborane catalysts... 

The titanium Lewis acid derived from diol (463) could be employed in catalytic amounts (0.1 mol equiv.) when molecular sieves were present (entries 2, 3). Under these conditions, cycloaddition of the crotonoyl dienophile was significantly more enantioselective compared with that of the acryloyl analog. On the other hand, both adducts (467a) as well as (467b) were obtained in 2% ee using the I wis acid (465) (0.1-0.2 mol equiv.), prepared in situ from bis-sulfonamide (464) and AlMes (entries 4, 5). 

The intramolecular aldol reaction in the presence of a titanium Lewis acid is a viable means of preparation of cyclic compounds. The cyclization is most conveniently performed between an enol silyl ether and an acetal, because the former is a reactive enol derivative and is readily prepared by silylation of the corresponding ketone in the presence of the acetal moiety in the same molecule. Equation (12) exemplifies a substrate undergoing intramolecular ring closure mediated by TiCU [74]. The conversion of sugar derivatives to carbocycles (called the Perrier reaction [75,76]) has been reported to occur in the presence of a Lewis acid. This process involves the aldol reaction between the enol ether and acetal moieties in the same molecule promoted by a titanium salt, as illustrated in Eq. (13) [77]. The similar reaction of a different type of substrate was also reported [78]. 

If the reaction between enol silyl ethers and a,/ -unsaturated ketones is attempted in the presence of a titanium Lewis acid, the mode of the reaction switches to 1,4-addition with reference to the unsaturated ketone [109-113]. The reaction of an enol silyl ether is shown in Eq. (30) [114]. Ketene silyl acetals react with a,j8-unsaturated ketones in similar 1,4-fashion, as exemplified in Eq. (31) [115]. Acrylic esters, which often tend to polymerize, are also acceptable substrates for a, -unsaturated carbonyl compounds [111]. A difluoroenol silyl ether participated in this cationic reaction (Eq. 32) [116], and an olefinic acetal can be used in place of the parent a-methylene ketone [111] to give the 1,5-diketone in good yield (Eq. 33) [117]. More results from titanium-catalyzed 1,4-addition of enol silyl ethers and silyl ketene acetals to a,f -unsaturated carbonyl compounds are summarized in Table 4. 

A chiral carbon present in the alcohol portion of acetals might control the stereochemistry of the allylation. A few examples conducted in the presence of a titanium Lewis acid are shown in Eqs (82) [225], (83) [226], and (84) [227]. In contrast, an allylsilane with a chiral auxiliary derived from arabinose on the silicon atom has been used for asymmetric synthesis, although diastereoselectivity was low [228],... 

Allylstannanes are frequently used as allylation reagents in the presence of a titanium Lewis acid [162,272-275]. The greater reactivity of allylstannanes than the corresponding allylsilanes toward electrophiles [272,275] often enables the use of a... 

A new synthetic design, based on a titanium Lewis acid consisting of two titanium centers in the same molecule, such as A in Fig. 9, has been reported. This titanium species is more active in allylation with an allylstannane than species B which has only one titanium center per molecule and is a conventional Lewis acid (Eq. 107) [281]. The intermediate C, in which double coordination of the oxygen functionality to both titanium atoms has been proposed, would account for the efficiency of the species A in this reaction. 

Analogous to the allylation with allylsilanes and -stannanes, the transformations, vinylallylation, propargylation, allenylation, alkenylation, alkynylation, and arylation, are viable by the use of an appropriate reagent in the presence of a titanium Lewis acid these are surveyed in the review articles cited both in the Introduction and in this section. The stereochemistry of the reaction of a (vinylallyl)silane in the presence of TiCU has been reported [234]. Equation (113) shows that the major reaction of this silane and isobutyraldehyde occurred mainly in the anti sense with a ratio of anti to syn attack of 90 10 at the terminus remote from the silyl group. Essentially the same stereochemical outcome was observed for the same reaction with the corresponding trimethylsilyl derivative. The intramolecular reaction with an acetal, however, proceeded less selectively the anti syn ratio was 60 40 (Eq. 114) [234]. 

Other investigations of titanium Lewis acids include a study of the molecular imprinting of a titanium salt according to Eq. (143) [356]. In the Diels-Alder reaction of Eq. (144), this polymer-immobilized titanium salt has catalytic activity only 3-5 times less that of the analogous complex of the type (ArO)2TiCl2 in solution. 

The Diels-Alder reaction of a relatively unreactive dienophile such as cyclopente-none can be effected with TiCU at a low temperature, although the exocyclic double bond of the product migrates to the more stable endo position (Eq. 145) [357]. A weaker Lewis acid, Ti(0-r-Pr)2Cl2, resulted in no reaction even under forcing conditions. Acceleration of reaction and the improvement of diastereoselectivity were achieved in a titanium Lewis acid-mediated intramolecular reaction as shown in Eq. (146) [358]. Other relevant Diels-Alder reactions promoted by titanium Lewis acids are summarized in Table 12. 

Table 12. Titanium Lewis acid-promoted Diels-Alder reactions.

Titanium Lewis acids effect formal [2 + 2] cycloaddition as shown in Eqs (158) [401] and (159) [402,403]. Subtly changing the reaction conditions and substrates alters the product of Eq. (159) from the cyclobutane to a dihydrobenzofuran derivative, as will be described below. The analogous hetero [2 + 2] addition of a chiral aldehyde to a silylketene proceeded stereoselectively in the presence of titanium tetrachloride to give the propiolactone, as shown in Eq. (160) [404]. The silyl group was removed by the treatment with KF. 

Preparation of heterocyclic compounds by coupling two constituents with a titanium Lewis acid is shown in Eqs (241) and (242). A C-labeled nitrogen heterocycle was synthesized by condensation of a keto-oxime and a-aminonitrile in the presence... 

Aziridination of an olefin has been performed with the reagent shown in Eq. (262) in the presence of Ti(0-i-Pr)4 [606,607], Excellent diastereoselectivity was observed. Other methods of aziridination to a, -unsaturated carbonyl compounds [608,609] or of imines [610-612] in the presence of a titanium Lewis acids are also available. 

Epoxide opening accompanied by the pinacol-type rearrangement of a carbon framework in the presence of a titanium Lewis acid has been used for the stereoselective synthesis of acyclic compounds [642,643], Equations (278) and (279) illustrate this transformation and exemplify the dependence of stereospecificity on the geometry of the epoxide... 

Titanium(IV) Lewis Acids 779 15.12 Titanium Lewis Acids in Radical Reactions... 

The reactions of organometallic reagents such as organolithium [696], -zinc [697-700], -magnesium [701], and -aluminum species [702] are facilitated by the presence of TiCU [9] as exemplified in Eq. (308) [703]. Even addition of a titanium compound to aldehydes was promoted in the presence of an extra amount of a titanium salt (Eq. 309) [704,705]. Titanium Lewis acids increase the reactivity of the a-position of a ketone (Eq. 310) [706] and the /3-position of an a,/3-unsaturated carbonyl compound towards nucleophiles (Eq. 311) [608,707-709]. The positive role of TiCU in the photo-hydroxymethylation of ketones and aldimines is ascribed to activation of methanol by the titanium salt (Eq. 312) [710]. 

Santora BP, Larsen AO, Gagne MR (1998) Toward the molecular imprinting of titanium lewis acids Demonstration of diels-alder catalysis. OrganometaUics 17 3138... 

Somewhat higher ees were also obtained in the presence of triisobutylaluminum. However, addition of titanium Lewis acids such as Ti(0-i-Pr)4 or TiCl4 resulted in the complete lose in enantioselectivity. 

Although it is a stoichiometric procedure, the intramolecular hetero-Diels-Alder reaction of l-oxa-l,3-butadienes, obtained in situ by a Knoevenagel condensation of aromatic aldehydes and N,N -dimethylbarbituric acid, is mediated by a chiral titanium Lewis acid 29 which has l,2 5,6-di-0-isopropylidene-a-D-glucofuranose as a ligand. The highest ee-value was obtained in the reaction of 30 with 31 in isodurene as illustrated in Scheme 13[26]. 

Similar to the ketene thioacetal. vinyl and alkynyl thioelhers react with 2-oxazolidinone derivatives of s ,/ -unsaturated acids to give the corresponding cyclobutanes and cyclobutenes with almost complete asymmetric induction0,31-35. From a [2 + 2] adduct, prepared by use of a chiral titanium Lewis acid, a carbocyclic analog of the four-membered nucleoside oxetanocin A has been readily prepared in optically pure form10. 

Similar applications of chiral titanium Lewis acid catalysts to asymmetric [2 + 2] cycloadditions, with up to nearly quantitative asymmetric induction, have employed 4-benzoquinones as additions and substituted styrene-type substrates11. In all of these asymmetric [2 + 2]-cvcload-dition reactions, the Lewis acid catalyst presumably is attached to peripheral functional groups and thus, similar to Lewis acid catalyzed Diels Alder reactions (see Section 1.5.8.3.5.4.), is only indirectly involved in the reaction course7. 

Applications of chirally modified titanium Lewis acids have been reported most cases use various acetal diols derived from tartrate as the chiral auxiliary26 33,31 90. Various methods of catalyst preparation are known, as well as the use of different types of dienes (open-chained, cyclopentadiene) and dienophiles (acroleins, acrylates, crotonates, fumarates and amides derived from oxazolidinone), including intramolecular cycloaddition30. Addition of 4 A molecular sieves can improve asymmetric induction31,34 (as observed with the Sharpless epoxidation, loc. cit 31 in ref 6) and shows remarkable solvent effects on enantioselectivity. This method has been applied to the asymmetric Diels-Alder cycloaddition of cyclopentadiene and open-chain dienes to acrylamides28, 35. 

Lewis acid 169. It was also shown that low temperatures increase the amount o chiral titanium Lewis acid 164. At 265.2 K a ratio of 169 164 = 1 2.85 and at 320. K of 1 1.67 was found. Furthermore, from the NMR spectra it seems evident thai the chiral Lewis acid 164 exists as a single species even under high pressure up tc 210 MPa. 

The reaction mechanism over the tin Lewis acid sites is therefore quite different from that over titanium Lewis acid sites. On the basis of Sn MAS NMR, the catalytic tin sites are thought to be within the framework. In the dehydrated solid the sites are tetrahedrally coordinated, and are able to bind with adsorbed molecules to become five- and six-fold coordinated. The Sn site activates the ketone rather than the hydrogen peroxide. The carbonyl oxygen from the ketone is thought to form a Lewis adduct with the framework tin, which is able to expand its coordination sphere as a so-called Criegee adduct (Scheme 9.10). ... 

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