Cyclizations titanium chloride

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus notable in that it is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4-phenyl-l-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenyl butyric acid) with methyl amine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20). 

With aluminum-chloride catalysts, the polymer structure is 80% cyclobutane units and about 5% cyclopropane units, the remainder being polyene units. With stannic chloride, we do not observe any cyclopropane units the polymer consists mainly of cyclobutane units (75%). The presence of methyl groups on cyclohexane shows that the other units possess partially isomerized and cyclized polyene structures. When using titanium chloride or ethyl aluminum chloride with traces of water as cocatalyst, the polymer consists mainly of cyclobutane units—that is, 60%, the demainder being cyclized see Equation 17. 

Chelation control of the intramolecular reaction between an allylsilane and an aldehyde or ketone has been carefully investigated. Excellent stereoselectivity was found for cyclization of B-oxo esters using titanium(IV) chloride as the Lewis acid, less good selectivity for cyclization of /l-diketones70. 

Tricyclic compounds can be obtained directly by annulation on to cyclic allylsilanes, using either ethylaluminum dichloride or titanium(IV) chloride as Lewis acids57. The stereochemical outcome of this particular cyclization is controlled by the relative configuration of the cyclic allylsilane. The reaction follows the usual anti" SE2 process for reactions of allylsilanes with electrophiles. Thus, the reaction was stereospecific, which makes it very useful for stereocon-trolled syntheses of complex ring systems57. 

A third method for the synthesis of cycl[3.2.2]azines, from iV-(aroylmethyl)pyridinium salts via indolizines, involves intramolecular (reductive) McMurry coupling of the latter. For example, 3,5-dibenzoylindolizines, obtained from 2-benzoyl-iV-phenacylpyridinium bromide as shown (Scheme 91), are cyclized using zinc and titanium(iv) chloride to give the 3,4-diphenylcyclazines 352 in high yield (>90%). The reaction cannot be applied, however, to... 

Cyclization of the acid chloride by means of aluminum chloride gives tetralone (19-2). This is then converted to its A -methylimine (19-3) by means of methylamine and titanium tetrachloride. That intermediate is next reduced with sodium boro-hydride to give a mixture of cis and trans aminotetralins (19-4). The tmns isomer tametraline (19-5) is separated by fractional crystallization of the hydrochloride salt [20]. Detailed pharmacological investigations showed that this compound owes its antidepressant action to the inhibition of reuptake of dopamine and norepinephrine from the synaptic cleft. 

An economical, biogenetically patterned, cyclization ofenamine ketones led to indolizidine alkaloids. The enamine (196) underwent cyclization and dehydration in methanol. Reduction to O-benzylipalbidine (191b) and debenzylation afforded ( )-ipalbidine (191a) (79-JCR(M)0413). Titanium(VI) chloride and silicon(IV) chloride may be the best Lewis acid catalysts for reactions of this type (81TL2127). 

The titanium trichloride-diethylaluminum chloride catalyst converted butadiene to the cis-, trans,-trans-cyclododecatriene. Professor Wilke and co-workers found that the particular structure is influenced by coordination during cyclization between the transition metal and the growing diene molecules. Analysis of the influence of the ionicity of the catalyst shows effects on the oxidation and reduction of the alkyls and on the steric control in the polymerization. The lower valence of titanium is oxidized by one butadiene molecule to produce only a cis-butadienyl-titanium. Then the cationic chain propagation adds two trans-butadienyl units until the stereochemistry of the cis, trans, trans structure facilitates coupling on the dialkyl of the titanium and regeneration of the reduced state of titanium (Equation 14). 

Reductive coupling of carbonyls to alkenes Titanium(IV) chloride-Zinc, 310 of carbonyls to pinacols Titanium(III) chloride, 302 Titanium(IV) chloride-Zinc, 310 of other substrates Samarium(II) iodide, 270 Reductive cyclization 2-(Phenylseleno)acrylonitrile, 244 Tributylgermane, 313 Tributyltin hydride, 316 Triphenyltin hydride, 335 Trityl perchlorate, 339 Reductive hydrolysis (see Hydrolysis) Reductive silylation Chlorotrimethylsilane-Zinc, 82... 

Surzur and Stella, in a paper mainly concerned with the free radical cyclization of pyrrolizidines, reported the formation of the benzindol-izidine 171 from iV-benzyl-iV-chloropentenylamine (170) when treated with titanium(III) chloride in aqueous acetic acid (Scheme 23),230... 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Cyclization of olefinic Se,0-heteroacetals 133 in the presence of titanium tetrachloride affords 4-chloroselenanes 134 in good yields (Scheme 13) <1994JOC1011>. The reaction proceeds through the formation of an a-selenocarbocation which reacts with the olefinic bond followed by chloride addition. The required precursors for the reaction can be readily prepared by reduction of the corresponding diselenides followed by alkylation. 

Since the introduction of the titanocene chloride dimer 67a to radical chemistry, much attention has been paid to render these reactions catalytic. This field was reviewed especially thoroughly for epoxides as substrates [123, 124, 142-145] so only catalyzed reactions using non-epoxide precursors and a few very recent examples of titanium-catalyzed epoxide-based cyclization reactions, which illustrate the principle, will be discussed here. A very useful feature of these reactions is that their rate constants were determined very recently [146], The reductive catalytic radical generation using 67a is not limited to epoxides. Oxetanes can also act as suitable precursors as demonstrated by pinacol couplings and reductive dimerizations [147]. Moreover, 5 mol% of 67a can serve as a catalyst for the 1,4-reduction of a, p-un saturated carbonyl compounds to ketones using zinc in the presence of triethylamine hydrochloride to regenerate the catalyst [148]. 

Cascade radical cyclization of A-chloro-A -allyl ( )-4,7-octadienamine 6 in the presence of titanium(lll) chloride gave in high yield (GC) a mixture of the bicyclic compounds 7 (two unseparable diastereomers with undetermined configuration) and the tricyclic compounds 8 (two diastereomers) in which the cis-syn-cis azatriquinane structure predominated14,0. The product 8 was obtained pure after column chromatography and its structure was assigned by high field ]H NMR. 

Several thiazolidines were synthesized via titanium tetrachloride catalytic cyclization <2005JOC227>. The reaction proceeds via an intramolecular attack on the nitrile by the aziridine nitrogen to provide bicyclic aziridinium intermediate 91. Subsequent ring opening by chloride yields thiazolidine 92 (Scheme 25). 

When the required 1,2-diaminoarencs are not readily available it is often possible to utilize o-nitroanilines as substitutes. They can be successively reduced or hydrogenated and then cyclized [82, 91, 133], or the cyclization and reduction processes can be combined. Suitable reducing agents are triethyl phosphite, iron pentacarbonyl, titanium(III) chloride, Raney nickel-hydrazine, palladium-carbon, bisulfite or dithionitc, and metal-acid [54, 134,135]. Thus, 4,5-dimethyl 2-nitroaniline heated at 90"C (1 h) with formic acid and sodium dithionitc gives 5,6-dimethyIbenzimidazolc in 92% yield [136]. 

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