m-Chlorobis(cyclopentadienyl)(dimethylaluminum)-m-methylenetitanium1

[67719-69-1]  · C13H18AlClTi  · m-Chlorobis(cyclopentadienyl)(dimethylaluminum)-m-methylenetitanium  · (MW 284.60)

(methylenating agent for alkenation of carbonyl compounds,2-4 particularly esters, ketones, and aldehydes; of low basicity and functions without epimerization at a-chiral centers)

Alternate Name: Tebbe reagent.

Physical Data: red solid.

Solubility: highly sol toluene, benzene, or dichloromethane; will dissolve in THF at low temperature (but not stable for prolonged periods in ethereal solvents). Nearly insol saturated hydrocarbons.

Form Supplied in: may be purchased as the pure solid or prepared from titanocene dichloride and trimethylaluminum.

Handling, Storage, and Precautions: the dry solid is air-sensitive and may be pyrophoric in air, especially when impure; it must be handled under an atmosphere of nitrogen or argon. The reagent is most conveniently stored and handled as a toluene solution; in this form the reagent is somewhat pyrophoric in air and must be handled using syringe and cannula techniques as practiced when using Grignard or alkyllithium solutions.

Tebbe Reagent as a Source of Cp2Ti=CH2.

The complex Cp2TiCH2.AlMe2Cl, commonly referred to as the Tebbe reagent,5 is a source of the reactive titanium methylene species Cp2Ti=CH2 as shown in eq 1. The methylene intermediate, formation of which is greatly accelerated by bases such as THF or pyridine, is useful for the methylenation of carbonyl compounds in a process similar to Wittig alkenation; the driving force is the high oxophilicity of titanium. The scope of reactivity is greater than with the corresponding phosphoranes;6 thus esters and amides are converted to vinyl ethers and enamines by the Tebbe reagent.2,7 The lower basicity of the Tebbe reagent offers further advantages over the Wittig procedure (see below). Although many examples of methylenation of unsaturated substrates are known, and carbon-carbon double bonds usually do not interfere, it should be noted that the Tebbe reagent will react with certain alkenes to form titanacyclobutanes.8 These titanacycles, of importance as intermediates in degenerate metathesis of terminal alkenes and ring-opening metathesis polymerization of strained cyclic alkenes,9 and as synthetic reagents themselves,1b have been studied in some detail. The most stable titanacyclobutanes are those derived from monosubstituted alkenes; even these will revert to free alkene and active methylene when heated to about 60 °C.10 Therefore mild heating may be used to improve yields of irreversibly formed methylenation products for certain substrates.3 Furthermore, use of excess Tebbe reagent will in certain cases lower the yield of alkene product.3,11

The reagent may be purchased as a pure solid, or synthesized as such using Schlenk line and glovebox techniques.5a,12 Since isolation of the Tebbe reagent is time-consuming, in situ preparations of the complex have been developed.3,13 It should be noted that in situ preparation produces a solution with one equiv of excess AlMe2Cl and often affords somewhat lower yields than the isolated reagent.1a,13a Typical conditions2,13a for use involve combining the reagent in toluene solution at low temperature with the substrate and a Lewis base such as THF and/or pyridine. After warming to room temperature, the solution is chilled and quenched with aqueous sodium hydroxide, diluted with ether, dried, filtered through Celite, and the product further purified, often by chromatography on neutral or basic alumina.

Tebbe methodology is specific for methylene transfer. However, approaches to analogous Group 4 metal reagents having substituted alkylidene units have been developed and show considerable promise.1a,14 Several other titanium-based reagents for methylene transfer have been developed.1a,15,16 A widely used system for methylenation of ketones15a is the still undefined mixture formed from Zn/CH2X2/TiCl4. Also, thermolysis of Cp2TiMe2 provides a clean aluminum-free source of Cp2Ti=CH2 and shows considerable synthetic promise.16 These various methylenation and alkylidenation processes have been comprehensively reviewed.1a

Methylenation of Aldehydes and Ketones.

The Tebbe reagent accomplishes methylenation of aldehydes and ketones.4,5a,11,17-23 Table 1 shows some representative conversions with yields for the Wittig reagent included where available; the titanium reagent affords consistently higher yields and is less sensitive to steric crowding than Methylenetriphenylphosphorane.4 It is particularly useful in preparation of exocyclic alkenes (e.g. entries 2, 4, 5 and 8); only in extremely hindered substrates such as fenchone (entry 3) is the reagent ineffective. Also, the titanium complex efficiently methylenates such readily enolizable ketones as b-tetralone (entry 4).

The Tebbe reagent will methylenate aldehydes and ketones without epimerization at a-chiral centers, as illustrated in eq (2).22 The relatively low basicity of this reagent also permits conversions such as eq (3), which gives almost exclusively b-elimination across the C(1)-C(2) bond when attempted by the Wittig method.11 When a large excess of Tebbe reagent is used in eq (3), gem-dimethylation occurs via a titanacyclobutane. Ketones with a,a-disubstitution (e.g. eq 4) will enolize rather than methylenate;23 these titanium enolates are not active in the aldol reaction. The Tebbe reagent shows synthetically useful selectivity for ketones in preference to esters, as in the conversion of entry 8 (where 15% methyl ketone byproduct was observed), which was unsuccessful using Zn/CH2X2/TiCl4 due to cyclopropanation. However, the Zn/CH2X2/TiCl4 mixture is much more widely used for ketone methylenation since in certain preparations it will not react with esters.1a

Methylenation of Esters and Lactones.

The greatest advantage of the Tebbe reagent is that, unlike phosphorous ylides, it may be used to convert esters and lactones to versatile enol ethers.2 The reaction is quite general and typically proceeds in good to excellent yield.3,7,24-50 Several representative conversions are presented in Table 2.

The procedure is tolerant of the acetal (entries 2 and 5) and cyano (entry 9) groups. Double bonds typically retain their stereochemistry (entry 8) and position. In a few instances, double bond migration has been reported upon workup;30,47 precautions to minimize such rearrangement are described.13a Other compatible functionalities include various siloxy groups,36,46 halide,44,48 and thioacetal.24 Ketone and ester groups may be simultaneously methylenated (entry 3), or a keto group may be preferentially methylenated with 1 equiv of reagent.7,21 Literature estimates of ketone versus ester selectivity are given as 4:1 in general2 and 25-30:1 for acetophenone against methyl benzoate.23 It has been observed that yields may differ depending on whether isolated Tebbe reagent is used or if the complex is generated in situ; for example, 94% in entry 1 compared with 68-70% by in situ methods.13a Nonetheless, yields are often excellent using the in situ reagent (e.g. entry 11 and others3,35), which is considerably less expensive than the isolated complex. Since enol ethers are not known to form titanacyclobutanes on reaction with the Tebbe complex, gem-dimethylation does not occur when excess reagent is employed.3

Methylenation of allyl esters (Table 2, entries 4, 9, 12, and 13) affords allyl vinyl ethers2,24,25,27,32,42-45,49 which are useful substrates for the Claisen rearrangement (e.g. eq 525 and eq 624a). Although the methylene group of the Ti complex is mildly basic, solutions of the reagent are Lewis acidic, particularly when an extra equivalent of AlMe2Cl is present from in situ reagent preparation. The acidic character of the reagent has been used to advantage in a mild one-pot synthesis of 1,5-dienes from allyl esters in which a Claisen rearrangement occurs under Lewis acid catalysis (eq 6 and entry 12).24a

The Tebbe complex has found frequent application in carbohydrate chemistry.26,31b,33,35,36

The titanium reagent allows transformations of esters without epimerization at a-chiral centers, as is illustrated in the methyl ketone preparation of eq 7.28b Cyclic carbonates may be methylenated as well (eq 8).1b

In at least one case where the Tebbe procedure is ineffective, presumably for steric reasons, an ester has been efficiently methylenated with Zn/CH2X2/TiCl4.38 However, hindered esters may be methylenated with the Tebbe reagent (e.g. entry 7).

Methylenation of Amides.

Amides have been converted to enamines of methyl ketones by the Tebbe reagent (eq 9).1a,b,7,51 No added base is required. Isolation of enamines is possible, or in situ alkylation may be performed.7 The reaction has been little developed.

Titanium Enolates from Acid Chlorides.

Acid chlorides have been reported to react with the Tebbe reagent to afford titanium enolate complexes (eq 10),52 although yields are much lower than those obtained using titanacyclobutane precursors.53 These enolate complexes of methyl ketones are known to participate in aldol reactions.53

Other Reactions of the Tebbe Reagent.

Silyl esters and thioesters are methylenated by the Tebbe reagent.1a The complex is known to react with alkynes to give stable titanacyclobutenes.54 Reaction with anhydrides gives enolate complexes which are not active in the aldol reaction.55 By contrast, unhindered imides may be methylenated in good yield with excellent selectivity in unsymmetrical cases.55 Nitriles react to afford vinylimidotitanium complexes, which have been studied in some detail.56 The reagent has found application in the preparation of various organometallic complexes.57

Related Reagents.

Bis(h5-cyclopentadienyl)(diiodozinc)(m-methylene)titanium; Bis(cyclopentadienyl)dimethyltitanium; Bis(cyclopentadienyl)-3,3-dimethyltitanacyclobutane; Dibromomethane-Zinc-Titanium(IV) Chloride; Diiodomethane.


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Daniel A. Straus

San Jose State University, CA, USA



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