Titanium tetrachloride catalyzed reaction

Hansen and colleagues177 used (+)-pantolactone as a chiral auxiliary to achieve asymmetric induction in the first step toward their synthesis of d.v-perhydroisoq uinol inc 278. The titanium tetrachloride catalyzed reaction between 1,3-cyclohexadiene (275) and chiral acrylate 276 proceeded with high diastereofacial selectivity to give 277 (94% de) in 75% yield (equation 77). 

In all instances a 2 1 mixture of anomers was obtained with the 3-D anomer predominating over the a-D anomer. The synthesis of 4 -acetamidoadenosine has been accomplished by the condensation of 4-acetamido-l,5-di-0-acetyl-2,3-di-0-benzoyl-4-deoxy-D-ribofuranose with chloromercuri-6-benzamido-purine using a titanium tetrachloride catalyzed reaction. ... 

There are several strategies that involve the use of transition metal catalysts in addition to the Mukaiyama reaction. Reaction of leucinal with 1,3-butanediol gave a mixture of 6.115 (in 9% yield) and 6.116 (in 71% yield). After the chromatographic separation of 6.116, the titanium tetrachloride catalyzed reaction with 3-trimethylsilyl-l-propene gave 6.117. Ozonolysis and oxidation gave lactam 6.118, which was converted to 6.101a in five steps (overall yield was 32% from 6.117). 

The action of water in the titanium tetrachloride catalyzed polymerization is paradoxical, since water at —60 to —80° was present only in the solid phase its solubility in hexane at these temperatures is in the order of 10-10 moles per liter (Plesch et al., 83). It was found to be essential that the water be present as an extremely fine dispersion such as might result from the rapid bubbling of moist air through the liquid at the low temperature. Addition of liquid water which formed lumps of ice in the reaction mixture did not initiate polymerization. It may be concluded that a fine dispersion is necessary in order that reaction with titanium tetrachloride can occur and a chain reaction is initiated ... 

Aqueous inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid and, preferentially, sulfuric acid, as well as some Lewis acids, e.g. boron trifluoride etherate and titanium tetrachloride, catalyze the a-addition of the isocyanides, yielding the a-hydroxycarboxamides (24) in 12-88% The catalysis of this reaction by acids is due to an enhancement of the electrophilic reactivity of the carbonyl compound (4). 

Both 2- and 3-aryl-P-alanine derivatives have been prepared by the Mukaiyama reaction of imines when catalyzed by titanium tetrachloride. The reaction of ketene silyl acetals with 0-alkyl imines is another source of aryl-substituted P-alanines.20 O-Substituted hydroxylamines (an "0-imine") have been used in this type of reaction. When 4.28 reacted with O-silylketene acetal 4.29, in the presence of... 

Conventional synthetic schemes to produce 1,6-disubstituted products, e.g. reaction of a - with d -synthons, are largely unsuccessful. An exception is the following reaction, which provides a useful alternative when Michael type additions fail, e. g., at angular or other tertiary carbon atoms. In such cases the addition of allylsilanes catalyzed by titanium tetrachloride, the Sakurai reaction, is most appropriate (A. Hosomi, 1977). Isomerization of the double bond with bis(benzonitrile-N)dichloropalladium gives the y-double bond in excellent yield. Subsequent ozonolysis provides a pathway to 1,4-dicarbonyl compounds. Thus 1,6-, 1,5- and 1,4-difunctional compounds are accessible by this reaction. 

Rates that are independent of aromatic substrate concentration have been found for reaction of benzyl chloride catalyzed by TiCl4 or SbFj in nitromethane. This can be interpreted as resulting from rate-determining formation of the electrophile, presumably a benzyl cation. The reaction of benzyl chloride and toluene shows a second-order dependence on titanium tetrachloride concentration under conditions where there is a large excess of hydrocarbon. ... 

Diastereoselection is also observed in the catalyzed [titanium tetrachloride (TiCI4)13, trimethyl-silyltrifluoromethanesulfonate (TMSTf)l4, zinc iodide (Znl2)15] reactions of silyl ketene acetal 1 with imines 2, The ami configuration of the product 3 dominates. 

Usually the stronger acids are also the more effective co-catalysts, but exceptions to this rule are known. Trichloroacetic acid, but not the equally strong picric acid, will co-catalyze the system isobutene-titanium tetrachloride in hexane.2 8 Some Lewis acid-olefin systems will not polymerize at all in the absence of a co-catalyst, an example being isobutene with boron trifluoride.2 4 This fact, together with the markedly slower reaction usual with carefully dried materials, has nourished the current suspicion that a co-catalyst may be necessary in every Lewis acid-olefin polymerization. It is very difficult to eliminate small traces of water which could act as a co-catalyst or generate mineral acid, and it may well be that the reactions which are slower when drier would not go at all if they could be made completely dry. 

Monochlorotitanium complex 418, prepared from (l/J,25 )-Af-(2,4,6-trimethylbenze-nesulfonyl)-2-amino-l-indanol and titanium tetraisopropoxide followed by treatment with titanium tetrachloride effectively catalyzed the cycloaddition of a-bromoacrolein to cyclo-pentadiene, affording 366 with 93% ee (equation 125)259. Catalyst 418 induced an ee of 90% in the reaction of isoprene with a-bromoacrolein. 

A number of methods that utilize enolsilanes directly in the aldol process with either aldehydes or acetals have been developed recently. These reactions may be catalyzed with either Lewis acids such as titanium tetrachloride (73) or with fluoride ion (74). 

Unlike boron fluoride, titanium tetrachloride does not catalyze the liquid phase polymerization of isobutylene under anhydrous conditions (Plesch et al., 83). The addition of titanium tetrachloride to a solution of the olefin in hexane at —80° failed to cause any reaction. Instantaneous polymerization occurred when moist air was added. Oxygen, nitrogen, carbon dioxide, and hydrogen chloride had no promoting effect. Ammonia and sulfur dioxide combined with the catalyst if these were added in small quantity only, subsequent addition of moist air permitted the polymerization to occur. Ethyl alcohol and ethyl ether, on the other hand, prevented the polymerization even on subsequent addition of moist air. They may be regarded as true poisons. 

A similar type of acid-catalyzed condensation of aldehydes with 4-methylene-2-oxetanone (diketene), giving 4-oxo-6-methyl-l,3-dioxins, has been patented (73GEP2149650). However, other work has established that <5-hydroxy-/3-keto acids or unsaturated keto acids are formed as the principal products (equation 24) (78CPB3877, 78CL409). The latter reaction probably involves electrophilic attack of the protonated aldehyde on the nucleophilic exocyclic methylene carbon atom of the diketone. A closely related reaction of acetals with diketene, catalyzed by titanium tetrachloride, gives the corresponding <5-alkoxy-/3-keto esters (74CL1189). 

The reaction of a-bromoacetals with trimethylsilylenolates catalyzed by titanium tetrachloride provides /3-alkoxy-y-bromoketones, which are useful furan precursors (Scheme 33) (75CL527). A new synthesis of acylfurans is exemplified by the formation of the 3-acetyl derivative (146) by heating the brdmoalkene (145) (78JOC4596). 2,2-Dimethyl-3(2//)-furanone (148) has been synthesized from 3-hydroxy-3-methylbutan-2-one treatment with sodium hydride and ethyl formate gave the hydroxymethylene derivative (147), which was cyclized and dehydrated to the furanone (148) with hydrochloric acid (Scheme 34) (71TL4891). O... 

Thenaldehyde (thiophene-2-carbaldehyde) is readily available via the Vilsmeier-Haack reaction of DMF with thiophene catalyzed by phosphorus oxychloride. The Sommelet reaction with 2-chloromethylthiophene also gives reasonable yields (63AHC(l)l). Likewise, thiophene is readily acylated with acyl anhydrides or acid chlorides (equation 14), using mild Friedel-Crafts catalysts, such as tin(IV) chloride, zinc chloride, boron trifluoride, titanium tetrachloride, mercury(II) chloride, iodine and even silica-alumina gels or low-calcium-content montmorillonite clays (52HC(3)l). 

The synthesis of p-lactams enantiomerically pure, via a multistep Gilman-Speeter type reaction [139] has been reported to be carried out with chiral oxazo-lidinones [140]. Titanium tetrachloride mediated condensation with imine gave an intermediate p-amino acyloxazolidinone, the major diastereomer of which could readily be purified by Si02 chromatography. Silylation and fluoride catalyzed cyclization gave the final p-lactam (Scheme 53). 

Three reactions, which were known from the literature to be catalyzed by Lewis acids were selected as test reactions. A, was the Reetz alkylation of silyl enol ethers with -butyl chloride for which titanium tetrachloride is known to be useful [52]. B, was the Diels-Alder reaction between furan and acetylenedicarboxylic ester for which aluminium trichloride is a good catalyst [53]. C, was a Friedel-Crafts acylation for which aluminium trichloride is the preferred catalyst [54]. The reactions are summarized in Scheme 6. 

The acid-catalyzed reaction of enol silyl ethers of cyclic ketones with optically active methyl 4-methylphenylsulfinate has been reported as a very efficient method for the synthesis of chiral a-sulfinyl cycloalkanones 212. Boron trifluoride-diethyl ether, titanium tetrachloride and tin(IV) chloride may all be used as catalysts, however, the reproducibility of this procedure has recently been questioned71. 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

Titanium tetrachloride and a tertiary amine are a useful catalyst for Knoevenagel condensation [149] as shown in Eq. (45) [150]. Because the reaction can be performed under mild conditions, acid-sensitive functional groups survive the reaction conditions and the optically active center at the enolizable position did not racemize (Eq. 45). More examples of the titanium-catalyzed Knoevenagel condensation are shown in Table 5. Alkylation of an (unsaturated) (iV,0)-acetal with active methylene compounds was performed analogously in the presence of TiCU and NEts (Eq. 46) [154]. Depending on the structure of the active methylene compounds, carbon-carbon bond... 

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