[110-18-9]  · C6H16N2  · N,N,N,N-Tetramethylethylenediamine  · (MW 116.24)

(bidentate tertiary amine Lewis base with good solvating properties; used as an additive to stabilize and activate organometallic reagents and inorganic salts; enhances the rate of metalation of a variety of aromatic and unsaturated systems as well as influencing the regiochemical outcome of these reactions; effective as a neutral amine in base catalyzed reactions)

Alternate Name: TMEDA.

Physical Data: bp 121 °C; d 0.781 g cm-3.

Solubility: very sol water, most organic solvents.

Form Supplied in: colorless liquid, typically of 99% purity as obtained commercially. Drying: for uses in conjunction with organometallic reagents, moisture exclusion is necessary. Removal of water is best achieved by refluxing over lithium aluminum hydride or calcium hydride for 2 h under nitrogen and distilling immediately prior to use.

Handling, Storage, and Precautions: TMEDA should be used directly after distilling. However, it may be stored under nitrogen and transferred by using a syringe and septum cap as required. For most applications the amine is removed during aqueous workup simply by washing with water owing to its high water solubility. Use in a fume hood.

Lithiation of Difficult Substrates.

TMEDA, through an erstwhile perception of enhanced chelating ability,1b but more likely through presentation of a more labile environment, activates organolithium reagents.1j n-Butyllithium forms hexamers in hexane but in the presence of TMEDA exists as a solvated tetramer.2 Thus the use of the n-butyllithium/TMEDA complex in hexane3 effects the dilithiation of Furan and thiophene,4 and lithiation of benzene,5 in high yields. The allylic deprotonation of unactivated alkenes is normally difficult to achieve with BuLi alone. However, in the presence of TMEDA, propene is monolithiated or dilithiated in the allylic position,6 and limonene is selectively lithiated at C-10.7 The resulting allylic carbanion and electrophiles such as Paraformaldehyde give functionalized products (eq 1).8

However, when vinylic metalation is desired, competing allylic deprotonation may occur. In general, thermodynamic acidity and the kinetic preference for vinylic deprotonation of cyclic alkenes decrease with increasing ring size.1h The stable alkane-soluble reagent n-Butyllithium-Potassium t-Butoxide-TMEDA in hexane9 metalates Ethylene with potassium10 and effects selective vinylic deprotonation of cyclopentene (eq 2),11 cyclobutene,12 norbornene, and norbornadiene.10

N-Alkyl- and N-arylpyrroles are readily a-lithiated.1c For example, N-methylpyrrole is deprotonated with Ethyllithium/TMEDA and the lithiated product has been treated with Carbon Dioxide to give the corresponding carboxylic acid in 70% yield (eq 3).13

Numerous examples exist in which TMEDA not only facilitates the lithiation of aromatic and heteroaromatic substrates but also controls the regioselectivity of lithiation.1c While tertiary benzamides are susceptible to nucleophilic attack by n-butyllithium to give aryl butyl ketones, the use of s-Butyllithium/TMEDA in THF at -78 °C provides the synthetically useful ortho metalated tertiary benzamide which may be treated with a large variety of electrophiles (eq 4).1d,14 Even with compounds having a second more acidic site the above conditions allow ortho lithiation to take place under kinetic control. Thus a p-toluamide is ortho lithiated with s-butyllithium/TMEDA in THF at -78 °C, but when Lithium Diisopropylamide is used as the base in THF at 0 °C the thermodynamically favored benzyllithium species is obtained (eq 5).15 The very marked influence of TMEDA on the lithiation of naphthyl methyl ether in hydrocarbon solvents is dramatically illustrated in the example in eq 6.16

The use of the s-butyllithium/TMEDA system in THF at -78 °C is widely employed for the lithiation of amide and thioamide derivatives adjacent to nitrogen.1f The resulting lithiated species undergo reaction with a variety of electrophiles such as aldehydes and ketones17a and dihalides (eq 7).17b

Ligand for Crystallographic Studies.

TMEDA markedly facilitates the isolation of otherwise inaccessible crystalline organolithium reagents suitable for structural determination by X-ray crystallographic means.18 In most cases, bidentate binding of the TMEDA ligand to the lithium ion is observed.

Control of Regioselectivity and Stereoselectivity.

The recognition by Ireland and co-workers19 that Hexamethylphosphoric Triamide has a profound effect on the stereochemistry of lithium enolates has led to the examination of the effects of other additives, as the ability to control enolate stereochemistry is of utmost importance for the stereochemical outcome of aldol reactions. Kinetic deprotonation of 3-pentanone with Lithium 2,2,6,6-Tetramethylpiperidide at 0 °C in THF containing varying amounts of HMPA or TMEDA was found to give predominantly the (Z)-enolate at a base:ketone:additive ratio of ca. 1:1:1, whereas with a base:ketone:additive ratio 1:0.25:1, formation of the (E)-enolate was favored (Table 1).20 This remarkable result contrasts with those cases where HMPA:base ratios were varied towards larger amounts of HMPA, which favored formation of the (Z)-enolate.21

However, TMEDA unlike HMPA, does not cause flow over from a carbonyl to conjugate addition manifold for many lithiated systems. For example, lithiated allylic sulfides undergo conjugate (or 1,4) addition to cyclopent-2-enone in the presence of HMPA (see Allyl Phenyl Sulfide), but in the presence of TMEDA, carbonyl addition only is observed.22 The perception that TMEDA is unable to form solvent-separated ion pairs required for conjugate addition in this case now requires reevaluation.1j,23 In the reaction of lithio a-trimethylsilylmethyl phenyl sulfide with cyclohexenone, HMPA promotes predominant conjugate addition, whereas TMEDA has little effect on the normal carbonyl addition pathway taken in THF alone (eq 8).24

Likewise, TMEDA in THF has little effect on the stereochemical outcome of the Horner-Wittig reaction of lithiated ethyldiphenylphosphine oxide with benzaldehyde in THF at low temperature compared to the reaction in THF alone: a very slight enhancement in favor of the erythro (anti) hydroxy phosphine oxide intermediate (erythro:threo from 85:15 to 88:12), thus leading to slightly enhanced (Z)-alkene formation, is observed. By contrast, a reaction in ether alone provides less of the erythro product (erythro:threo 60:40).25 These examples serve to emphasize current thought that TMEDA is not a good chelating agent for lithium in relation to THF itself.1j It is noteworthy that the substitution of methyl in TMEDA by chiral binaphthylmethyl ligands generates a reagent which efficiently catalyzes asymmetric addition of butyllithium to benzaldehyde in ether at low temperature (eq 9).26

Butylmagnesium bromide in THF in the presence of excess TMEDA undergoes addition to a chiral crotonamide derivative to give the conjugate adduct in modest diastereomeric excess (67%) compared with 16% in the absence of TMEDA.27 On the other hand, diastereoselection in the alkylation of enolates of chiral diamides derived from piperazines in THF containing TMEDA was minimal, with better results being provided by HMPA.28

Stabilization and Activation of Organometallic Reagents.

The development and use of organocopper reagents as nucleophiles in the conjugate addition to enones is an important area of organic synthesis. It has been found that the reactivity of aryl- and alkylcopper reagents is dramatically improved through the use of Chlorotrimethylsilane and TMEDA.29 The TMEDA not only stabilizes and solubilizes the organocopper reagent but also facilitates the trapping of the resulting enolates, thereby affording silyl enol ethers in excellent yields.29a Such a role is also played by HMPA30 and 4-Dimethylaminopyridine.30b However, the low toxicity and cost of TMEDA makes it an attractive alternative. Conjugate addition of Lithium Di-n-butylcuprate to methyl 2-butynoate in diethyl ether provides a 74:26 mixture of (E)- and (Z)-alkylated enoates, whereas in the presence of TMEDA this ratio increases to 97:3. Stereoselectivity of the conjugate addition of the copper reagent derived from butylmagnesium bromide and Copper(I) Iodide to ethyl pentynoate in diethyl ether is also enhanced when TMEDA or pyrrolidone are used as additives, to give the (E)- and (Z)-enoates in a ratio of 99:1. In contrast, the use of HMPA affords a selectivity of only 78:22 for the (E)-isomer.31

The preparation of a trifluoromethylvinyl anion equivalent has been described in which the vinyl bromide is converted into the zinc reagent with Zinc/Silver Couple in the presence of TMEDA. The conversion proceeds very cleanly to afford a thermally stable vinylzinc bromide-TMEDA complex which can undergo reactions with electrophiles. TMEDA is essential for the conversion (eq 10).32

The intramolecular insertion of unactivated alkenes into carbon-lithium bonds to give cycloalkylmethyllithium compounds provides a high-yielding alternative to analogous radical cyclizations.1g,33 In many cases the addition of Lewis bases such as TMEDA increases the rate of cyclization1g,33 and dramatically improves those cyclizations which are otherwise sluggish at room temperature (eq 11).34

Open chain allylic alcohols add organolithium reagents in the presence of TMEDA. The reactions are regio- and stereoselective; the suggestion is made that the TMEDA complexes the alkoxide lithium counterion, allowing the alkoxide to orientate the incoming organolithium reagent and stabilize the resulting intermediate (eq 12).35

Inorganic Complexes useful in Organometallic Reactions and Organic Synthesis.

The complexing properties of TMEDA have made it possible to prepare and handle salts which are otherwise air and moisture sensitive. Thus Zinc Chloride in the presence of one equivalent of TMEDA forms a crystalline air stable solid, ZnCl2.TMEDA,36 which with three equivalents of an alkyllithium reagent is converted into trialkylzinclithium. Likewise, CuI and TMEDA react to form the CuI.TMEDA complex,29 a stable solid which is used for the preparation of stabilized organocopper reagents. The rate of CuI-catalyzed oxidative coupling of terminal alkynes in the presence of oxygen to form diynes is considerably increased by using TMEDA as a solubilizing agent for Copper(I) Chloride.37 Magnesium hydride, rapidly acquiring widespread recognition as a versatile reducing agent (see Magnesium Hydride-Copper(I) Iodide), is prepared from phenylsilane and Dibutylmagnesium in the presence of TMEDA to give a very active THF-soluble complex free of halide or impurities derived from the usual reducing agents such as Lithium Aluminum Hydride.38 TMEDA (see also 1,4-Diazabicyclo[2.2.2]octane) forms insoluble adducts with boranes and alanes. In particular, the formation of air-stable adducts with monoalkyl boranes is of synthetic usefulness. The free monoalkyl borane may be regenerated by treating the adduct with Boron Trifluoride Etherate in THF and filtering off the newly formed TMEDA.2BF3 precipitate.1e

Base Catalyzed Reactions.

TMEDA can be monoprotonated (pKa 8.97) and diprotonated (pKa 5.85).39 Titanium enolate formation from ketones and acid derivatives has been achieved by using Titanium(IV) Chloride and tertiary amines including TMEDA in dichloromethane at 0 °C.40 The reactive species, which is likely to be a complex with the tertiary amine, undergoes aldol reaction with aldehydes to form syn adducts with high stereoselectivity (eq 13).

In the case of TMEDA, stereoselection in favor of the syn product (98:2) is enhanced over that achieved with Diisopropylethylamine (94:6).40 Along with bases such as Triethylamine and ethylisopropylamine, TMEDA facilitates the preparation of cyanohydrin trimethylsilyl ethers from aldehydes and Cyanotrimethylsilane.41 It has been suggested that coordination by nitrogen induces formation of an active hypervalent cyanation intermediate from cyanotrimethylsilane. The conjugate addition of thiols to enones has been successfully catalyzed by using TMEDA in methanol at room temperature, as exemplified by the reaction of 10-mercaptoisoborneol and 4-t-butoxycyclopentenone (eq 14).42 In this case the relative mildness of the reaction conditions prevents subsequent elimination of t-butoxide from occurring to give the unwanted enone.

Related Reagents.

Hexamethylphosphoric Triamide; N,N,N,N,N-Pentamethyldiethylenetriamine; Potassium Hydride-s-Butyllithium-N,N,N,N-Tetramethylethylenediamine; (-)-Sparteine.

1. (a) Agami, C. BSF(2) 1970, 1619. (b) Wakefield, B. J. The Chemistry of Organolithium Compounds; Pergamon: Oxford, 1974. (c) Gschwend, H. W.; Rodriguez, H. R. OR 1979, 26, 1. (d) Beak, P.; Snieckus, V. ACR 1982, 15, 306. (e) Singaram, B.; Pai, G. G. H 1982, 18, 387. (f) Beak, P.; Zajdel, W. J.; Reitz, D. B. CRV 1984, 84, 471. (g) Klumpp, G. W. RTC 1986, 105, 1. (h) Brandsma, L.; Verkruijsse, H. Preparative Polar Organometallic Chemistry 1; Springer: Berlin, 1987. (i) Advances in Carbanion Chemistry; Snieckus, V., Ed.; JAI: Greenwich, CT, 1992; Vol. 1. (j) For a review and critical analysis of TMEDA complexation to lithium, see: Collum, D. B. ACR 1992, 25, 448.
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Richard K. Haynes

Hong Kong University of Science and Technology, Hong Kong

Simone C. Vonwiller

The University of Sydney, NSW, Australia

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