Low temperature lithiations

The use of chiral auxiliaries has been developed into elegant three-step sequences to achieve high ee s (Figure 2). In the general scheme a ketone is derivatized with a chiral amine. Low temperature lithiation and alkylation followed by hydrolysis produces the alkylated ketone in moderate to excellent ee s. The auxiliaries most often used are (S)-valine tert-butyl ester (Koga), l-amino-2-methoxymethylpyrrolidine (Enders) and (S)-2-amino-1-... 

Regioselective substitution reactions of a series of 2- and 3-hydroxybiaryls including BINOL have been performed via a new directed orf/io-metallation procedure.75 O-Aryl AMsopropylcarbamates, conveniently prepared from phenols and isopropyl isocyanate, have been temporarily and in situ N-protected by means of silyl inflates to form stable intermediates for low-temperature lithiation reactions using n-BuLi-TMEDA in diethyl ether. The IV,IV-dialkyl aryl O-sulfamate has been reported as a new directed metallation group.76... 

Functionalised vinyl lithiums prepared from vinyl chlorides are a little more stable 18 can be made and functionalised at -78 °C for example (though the corresponding alkoxy-substituted vinyllithiums are unstable),30 and the low-temperature lithiation of 19 provides a d3 reagent 20.31... 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

In an extensive temperature study on the lithiation of 2-methylthiazole (157) J. Crousier reported (441) that three lithio salts are formed independently, and not through proton-metal equilibration, at low temperature (—78 C, as shown in Scheme 77). The 4-lithio derivative (160) is... 

Lithiated areneacetonitriles react with a,/i-unsaturated ketones at low temperatures using short reaction times to give both 1,2- and 1,4-adducts. The 1,2-addition is reversible and under thermodynamic control (higher temperatures and longer reaction times) only the 1,4-adducts, i.e., <5-oxonitriles, arc obtained. When lithiated arylacetonitrile is added to 2-substituted 2-cy-cloalkenones in THF or in THF/HMPA mixtures at — 70-0°C, followed by protonation or alkylation under kinetically controlled conditions, predominantly cis- or fnms-2,3-disubstitut-ed cycloalkanones respectively, are obtained. 

Recently, nitration of organolithiums and Grignards with N204 has been developed for the preparation of certain kinds of nitro compounds (Eqs. 2.14 and 2.15).31 The success of this process depends on the reaction conditions (low temperature) and the structure of substrates. For example, 3-nitrothiophene can be obtained in 70% overall yield from 3-bromothiophene this is far superior to the older method. 3-Nitroveratrole cannot be prepared usefully by classical electrophilic nitration of veratrole, but it can now be prepared by direct o>7/ o-lithiation followed by low-temperature N204 nitration. The mechanism is believed to proceed by dinitrogen tetroxide oxidation of the anion to a radical, followed by the radical s combination. 

An important conclusion that these authors drew based on their polarization and EIS studies is that the properties of the SEI film on a graphite anode surface play a far more decisive role in determining the kinetics of the lithiation/delithiation at low temperatures than does the bulk ion conductivity, although it is necessary for the latter to achieve a... 

Fluorinated carbonates were also used by Smart et al. as low-temperature cosolvents (Table 12), in the hope that better low-temperature performances could be imparted by their lower melting points and favorable effects on SEI chemistry. Cycling tests with anode half-cells showed that, compared with the ternary composition with nonfluorinated carbonates, these fluorinated solvents showed comparable and slightly better capacity utilizations at room temperature or —20 °C, if the cells were charged at room temperature however, pronounced differences in discharge (delithiation) capacity could be observed if the cells were charged (lithiated) at —20 °C, where one of these solvents, ethyl-2,2,2-trifluoroethyl carbonate (ETFEC), allowed the cell to deliver far superior capacity, as Figure 63 shows. Only 50% of the capacity deliverable at room temperature was... 

Benzotellurophene (R = H) is stable only in benzene solution at low temperature, but the diester and disulphonyl derivatives (obtained by the bis-lithiation and subsequent reaction with alkyl chloroformates and p-toluenesulphonic anhydride) as well as the nitroderivative are more stable. 

Aromatic substrates containing Lewis basic substituents can undergo ort/io-lithiation. Quenching these anions with dinitrogen tetroxide at low temperature is an example of nucleophilic aromatic nitration." Similar examples have been reported with anions generated from Grignard reactions with arylhalides." ... 

Laterally lithiated tertiary amides are more prone to self-condensation than the anions of secondary amides, so they are best lithiated at low temperature (—78 °C). N,N-Dimethyl, diethyl (495) and diisopropyl amides have all been laterally lithiated with aUcyllithiums or LDA, but, as discussed in Section I.B.l.a, these functional groups are resistant to manipulation other than by intramolecular attack" . Clark has used the addition of a laterally lithiated tertiary amide 496 to an imine to generate an amino-amide 497 product whose cyclization to lactams such as 498 is a useful (if rather low-yielding) way of building up isoquinoline portions of alkaloid structures (Scheme 194) ". The addition of laterally lithiated amines to imines needs careful control as it may be reversible at higher temperatures. ... 

A similar cyclization can result from lithiation of an isonitrile lithiation of 553 requires two equivalents of LDA and the organolithium 554 can either be trapped with other electrophiles at low temperature or warmed to give an indole 555 (Scheme 219) . It is quite clear that isonitriles activate purely by conjugation, and indeed they promote deprotonation of methyl groups para to an isonitrile just as well as ortho. The ease with which isonitriles can be made from formamides suggests that these methods could be rather more widely used than they are. 

By carrying out a subsequent ortholithiation at low temperature, it was possible to show that tertiary benzamides also react atroposelectively in laterally lithiation-electrophilic quench sequences . Either atropisomer 575 or 578 could be made starting from 573 or 576 (Scheme 231). 

The bromide-lithium exchange of l,l-dibromo-2,2-diphenylethylene (88) was thoroughly examined by Maercker and coworkers. It could be shown that the number of side-products drastically decreases when LiDBB instead of metallic lithium is used as lithiation agent. The reaction was performed in THF at low temperatures by addition of the solution of the geminal dibrominated aUcene to the solution of LiDBB (Scheme 32). By this method, l,l-dilithio-2,2-diphenylethylene (89) could be obtained in 36% yield together with the 1,4-dilithium compound 48 and monolithiated 47 (51 and 2%, respectively). The yields were determined after trapping the reaction mixture with dimethyl sulphate. 

Three different di- and trilithiated phenylmethanes 93, 95 and 97 were generated by Baran Jr. and Lagow. Dichlorodiphenyhnethane (92), dichlorophenyhnethane (94) and trichlorophenyhnethane (96) were reacted with the appropriate amount of f-butyllithium in THF at very low temperatures. Except for dihthiodiphenyhnethane (93), the observed yields were very low, verified by deuteriolysis of the lithiated compounds (Scheme 33). 

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