Aldol reactions Titanium chloride

In the Mukaiyama variation of the aldol reaction, 3-benzoyloxy-2-trimethylsiloxy-l-butene adds to 2-methylpropanal in a stereoselective manner. Best results are obtained in the presence of titanium(IV) chloride, giving the adducts 9/10 in a diastereomeric ratio of 92 8. Hydrolysis of the benzoyl group and subsequent oxidative cleavage of the 1,2-diol moiety liberates / -hy-droxycarboxylic acids593. 

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

Magnesium, 235 Samarium(II) iodide, 270 Titanium(IV) chloride, 304 Addition reactions to carbonyl groups—Addition of functionalized CARBON NUCLEOPHILES (see also Aldol reaction and other specific condensation reactions, Meth-ylenation, Peterson Olefination, Refor-matsky reaction, Wittig reaction, Wittig-Horner reaction)... 

Triphenylphosphine-Diethyl azodicar-boxylate-Lithium halides, 332 Mukaiyama aldol reaction 1-Methoxy-l, 3-bis(trimethylsilyloxy)-l, 3-butadiene, 178 Tin(II) chloride, 298 Titanium(IV) chloride, 304 Trityl perchlorate, 339 Murahashi reaction N,N-Methylphenylaminotributylphos-phonium iodide, 191... 

The aldol reactions of the titanium Z-enolates proceeded smoothly with various aldehydes precomplexed with titanium chloride at -78° C. The diastereose-lectivity is high to excellent, with the single exception of benzaldehyde. The high degree of diastereoselection associated with this current asymmetric anti-aldol process can be rationalized by a Zimmerman-Traxler type of six-membered chairlike transition state Al9fl (Scheme 2.2r). The model is based on the assumptions that the titanium enolate is a seven-membered metallocycle with a chairlike conformation, and a second titanium metal is involved in the transition state, where it is chelated to indanolyloxy oxygen as well as to the aldehyde carbonyl in a six-membered chairlike transition-state structure. 

Now the aldol reaction can occur the positive charge on the titanium-complexed carbonyl oxygen atom makes the aldehyde reactive enough to be attacked even by the not very nucleophilic silyl enol ether. Chloride ion removes the silyl group and the titanium alkoxide captures it again. This last step should not surprise you as any alkoxide (MeOLi for example) will react with Me3SiCl to form a silyl ether. 

Aldol Reaction. In addition to the allyl derivatives (2) (eq 1), titanium ester enolates derived from chloride (1) react with aldehydes, affording aldol products after hydrolysis. Compared to the analogous reagents prepared from Chlow(cyclopentadienyl)bis[3-0-( 1,2 5,6-di-0-isopropylidene-a-D-glucofuranosyl)]-titanium the enantioselectivity of these... 

The related lactate-derived ketones, 44 [27] and 45 [29], are useful auxiliaries for boron- and titanium-mediated syn aldol reactions, respectively (Scheme 9-14). The effect of the protecting group in both cases is notable. For ketone 44, the use of the boron chloride reagent unexpectedly afforded the syn adduct with good control... 

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n < AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn... 

Tin(IV)-chloride-mediated double aldol reaction of acyclic ketones is rendered stereoselective by a chiral phosphine oxide, (5)-BE JAPO it is proposed that the catalyst controls the first aldol and the substrate controls the second. Another chiral diphosphine oxide, this one based on thiophene, catalyses direct aldols in high delee Chiral a-silyloxy ketones derived from lactate (61) undergo titanium(IV)-mediated aldols giving diastereomerically pure syn-syn adducts (62) in high yield, irrespective of the alkyl groups fianking the silyl or carbonyl. 

A silver salt dramatically reverses the diastereoselectivity of a titanium-chloride-mediated vinylogous Mukaiyama aldol reaction of a chiral vinylketene silyl N, 0-acetal with ethyl glyoxolate. ° ... 

Aldol Reactions of Ester Derivatives. The titanium(IV) chloride-catalyzed addition of aldehydes to CT-silyl ketene acetals derived from acetate and propionate esters proceeds with high stereoselectivity. Eormation of the silyl ketene acetal was found to be essential for high diastereoselectivity. Treatment of the silyl ketene acetal, derived from deprotonation of the acetate ester with LICA in THE and sUyl trapping, with a corresponding aldehyde in the presence of TiCLj (1.1 equiv) afforded the addition products in 93 7 diastereoselectivity and moderate yield (51-67%). Similarly, the propionate ester provides the a/jfi-aldol product in high antilsyn selectivity (14 1) and facial selectivity (eq 4). 

Under either the catalytic (eq 1) or the stoichiometric conditions (eq 2), the reagent undergoes addition to chiral aldehydes with complete reagent control , i.e. the stereochemistry of the aldol reaction is totally controlled by the chiral catalyst regardless of the inherent diastereofacial preference of the chiral aldehydes (eq 4). Titanium(IV) chloride and tm(TV) chloride mediate the addition of the title reagent to chiral a-alkoxy aldehydes and -alkoxy aldehydes with complete chelation control (eq 5), whereas the corresponding silyl ketene acetal is unselective. 4... 

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]. 

The early tvork in the field of titanium enolate acetate aldol reactions tvas conducted by Braun in a general investigation of acetate aldol reactions [12]. The enoiates tvere generated from chiral acetamide 16 by transmetalation of the lithium enolate tvith triisopropoxytitanium chloride or titanium tetrachloride, as sho vn in Table 2.3. They reported moderate selectivity for the reaction vith benzaldehyde. 

Typical Procedure for Titanium(IV) Chloride-catalyzed Aldol Reaction of Silicon Enolates (Eq. (23)) [20b]... 

In the presence of titanium(IV) chloride, silyl dienol ether 55 derived from an a,/i-unsaturated aldehyde reacts tvith acetal 54 selectively at the y-position to give d-alkoxy-a,j5-unsaturated aldehydes 56, albeit in lotv yields. Because titanium(IV) chloride is strongly acidic, polymerization of silyl dienol ether 55 proceeds. In these reactions addition of tetraisopropoxyti-tanium(IV) to titanium(IV) chloride increases the yield dramatically [28a] -vitamin A is successfully synthesized by utilizing this aldol reaction of silyl dienol ether 55 (Scheme 3.2) [28b]. 

Initially, the titanium(IV) chloride-mediated aldol reaction of silyl enolates tvith aldehydes tvas investigated [20] and a catalytic amount of trityl salt 60 (e.g. trityl perchlorate) vas found to promote the aldol reaction (Eq. (27)) [35]. Whereas the original reaction is performed by using a stoichiometric amount of titanium(IV) chloride, 5-10 mol% trityl salt is sufficient to drive the aldol reaction to completion. One interesting finding in this catalytic reaction is that the silicon enolate reacts vith aldehydes to give the corresponding aldol adducts as their silyl ethers 61. 

Aldol Reactions.—The recent use of metalated derivatives of protected aldehydes and ketones in cross-aldol reactions is referred to elsewhere (see refs 68, 72, 73, and 147). Alternative methodology for accomplishing cross-aldol reactions involves the utilization of vinyloxyboranes, and a new method for preparing the latter compounds from ketones has been reported (Scheme 25)." The scope of the related and more established cross-aldolization process involving the titanium(iv) chloride-promoted reaction of silyl enol ethers with aldehydes and ketones has been investigated, and the reaction has been utilized in the synthesis of two naturally occurring compounds. ... 

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