Ketones directed lithiation

Thiophene is sufficiently acidic to be directly metallated upon treatment with n-BuLi (see Figure 4.1). This direct lithiation can also be realized with polystyrene-bound 3-(alkoxymethyl)thiophene [96]. The resulting organolithium compounds react as expected with several electrophiles, such as amides (to yield ketones), alkyl halides, aldehydes, and Me3SiCl [96]. 

Hydroxyisocoumarins are accessible from 3-hydroxybenzyl ketones using directed lithiation as the key step (95G 111) and isocoumarins have been prepared from 2-iodobenzoic acid and alkynes through a Pd-mediated annulation (95JOC3270, 3711). The cyclisation of tertiary alcohols derived from the reaction of o-cyanobenzyllithium with aldehydes and ketones yields 3,4-dihydroisocoumarins (95S1102). 

Directed lithiation. 2-Arenesul gioselective fashion, furnishing thio 157-96%). 3-Halopyridines, includm lithiation and regioselective reaction that 3-chloro-4-iodopyridine generate t-BuLi. Halogen dance is also obsersx Vinyl esters are silylated at the esters of silyl ketones. The regiosel and the ability of the lithio derivative tion with suitable acceptors are expio cyclopentenones. ... 

One representative synthesis of prothioconazole starts [95] with the addition of the Grignard derivative of 2-chlorobenzyl chloride on the carbonyl double bond of chloromethyl 1-chloro-cyclopropyl ketone (Scheme 17.19). The untouched chlorine atom of the chloromethyl group is then classically substituted with 1,2,4-triazole. From this intermediate, one way to obtain the 2,4-dihydro-3H-l,2,4-triazole-3-thione of prothioconazole is by direct lithiation of the 1,2,4-triazole at position 5 with n-butyl lithium and reaction with sulfur. The commercially available compound is a mixture of two enantiomers (chirality of the quaternary carbon bearing the hydroxy group). 

A full report has appeared on the direct lithiation of NN-di-isopropylformamide by t-butyl-lithium and the use of the acyl carbanion thus obtained in the synthesis of a-keto-amides. The lithium enolate of NN-dimethylacetamide has been isolated for the first time, as a white solid, and has been shown to react well with a usual range of electrophiles. A Canadian group have also discussed the synthesis and reactions of such enolates, in particular their behaviour with ketones from which 70% yields of jS-hydroxyamides can routinely be obtained. " These enolates when generated as in the above methods, using lithium di-isopropylamide, also afford good yields of a-(methylthio)-amides when treated with dimethyl disulphide, in contrast to when sodium in liquid ammonia is used as base, which results in polysulphenylation of the amide. ... 

The addition of allylic organometallic reagents to aldehydes and ketones is another route to -unsaturated alcohols. A new preparation of allyl-stannanes, and hence of allyl-lithium species (Scheme 13), is useful where direct lithiation to... 

Preparation from 4-hydroxy-3-meth-oxybenzyl methyl ether (SMI) in two steps first, direct lithiation of SMI with n-butyl lithium in tetrahydrofuran at r.t., followed by quenching with 2,4-dimethoxybenzaldehyde. Then, oxidation of the 8-(2,4-dimethoxyphenyl)-2,7-dimethoxybicyclo[4.2.0]octa-l,3,5-triene-3,8-diol formed (SM2) (good yield) [1171]. Actually, SM2 was quantitatively converted back into the expected ketone by heating a toluene solution to reflux for 14 h [1171]. m.p. and Spectra (NA). 

Since the first reported directed aldol condensation using lithiated imines1. few methods concerning the diastereo- and enantioselectivity of their addition to aldehydes and ketones have been published. 

This is known as the directed aldol reaction. Similar reactions have been performed with oc-lithiated dimethylhydrazones of aldehydes or ketones and with a-lithiated... 

Although lithium p-lithioalkoxides can also be generated from p halo alcohols by deprotonation and subsequent reductive lithiation of the carbon-halogen bond73 8 or from p-halo ketones by organolithium addition to the carbonyl group followed by reductive lithiation,8 the current method is more direct as well as more convenient, since epoxides are readily available either commercially or by a variety of procedures. 

Similarly, polysulfone has been sulfophenylated by lithiation and anionic reaction with 2-sulfobenzoic acid cyclic anhydride (Figure 12). This provides another method to modify polysulfones by attaching pendant sulfonated phenyl groups via ketone links. It would be interesting to see if the phase separation in these materials was affected by the additional functionality of the ketone or the pendant attachment of the sulfonic acid, as opposed to direct attachment of ionic groups to the aromatic polymer backbone. 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

In late 1975, Enders et al.156) started a research project directed towards the development of a new synthetic method for asymmetric carbon-carbon bond formation. A new chiral auxiliary, namely the (S)-proline derivative SAMP (137), was allowed to react with aldehydes and ketones to give the hydrazones (138), which can be alkylated in the a-position in an diastereoselective manner 157,158). Lithiation 159) of the SAMP hydrazones (138), which are formed in excellent yields, leads to chelate complexes of known configuration 160). Upon treatment of the chelate complexes with alkyl halogenides the new hydrazones (139) are formed. Cleavage of the product hydrazones (139) leads to 2-alkylated carbonyl compounds (140). 

Ketones may direct lateral lithiation even if the ketone itself is enolised enolates appear to have moderate lateral-directing ability. Mesityl ketone 433, for example, yields 434 after silylation - BuLi is successful here because of the extreme steric hindrance around the carbonyl group.396 The lithium enolate can equally well be made from less hindered ketones by starting with a silyl enol ether.396... 

A more direct access to imidoyllithiums was to perform the lithiation of imidoyl chlorides 72 with lithium and substoichiometric amounts of naphthalene at low temperatures so that intermediates 73 were generated (Scheme 19)65,81. Aldehydes, ketones and acyl chlorides have been used as electrophilic reagents to afford imines 74 or the corresponding ketones, depending on the hydrolysis conditions. 

Simple enamines cannot be deprotonated directly at the a-position due to their low acidity, but starting from a-chloroenamines 685, a-lithioenamines 686991 have been prepared by chlorine-lithium exchange using an arene-catalyzed lithiation992. The treatment of compounds 685 with an excess of lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl (DTBB) in THF at —90 °C allowed the preparation of intermediates 686, which were trapped with a variety of electrophiles (Scheme 177). For aldol reactions, the arene-catalyzed lithiation has to be performed in the presence of aldehydes (Barbier conditions) at —40 °C. These adducts were transformed into a-hydroxy ketones after acid hydrolysis with hydrochloric acid or silica gel. 

Deactivation of the amide carbonyl by N-lithiation directs the second lithiation to the ortho position to the amide group. The dilithio compound is stabilized by intramolecular chelation. Larcheveque and coworkers used a chiral amide that was obtained from the reaction between an optically active epihydrin and an anhydride for the asymmetric synthesis of ketones or of substituted acids76 (equation 13). 

Employing an excess of the organometallic reagent (2 equiv) at 100 °C resulted in the formation of ketopyrrole (S)-79 in 87% yield. Obviously, compound (S)-79 is produced by successive N-acylation, t>-directed metallation and N,C-acy migration. Nucleophilic ring-opening reaction of the lactone (S)-77 with A -methylpyrrole lithiated in 2-position (with Bu Li/TMEDA) proceeded smoothly furnishing the ketone (S)-79 in 62% yield. 

Direct metallation of methylenecyclopropane with butyllithium in THF affords meth-ylenecyclopropyllithium. This reacts with carbonyl electrophiles such as aldehydes, ketones and lactones by ring alkylation to give selectively 2-methylenecyclopropyl carbinols. No products of exo alkylation are isolated. Other bases such as r-BuOK and KH do not deprotonate methylenecyclopropane. Use of diethyl ether as the solvent, instead of THF, significantly reduced the rate of lithiation. Similar reaction of the lithium reagent with ethylene oxide gave 2-(2-methylenecyclopropyl)ethanol (equation 294) In the reaction with C-labeled ethylene oxide the addition of TMEDA to the reaction mixture is recommended. ... 

Scheme 16.11 shows the completion of the total synthesis of azaspiracid-1, which followed with slight modifications, the synthesis of the originally proposed structure of azaspiracid-1 (la). This chemistry was also carried out with the corresponding ABCD enantiomer in similar yields. Thns, lithiation of dithiane 51 (n-BuLi n-BnjMg) followed by addition into pentafluorophenol ester 68 resulted in CJ-C27 ketone 69 (50% yield). Ketone 69 was then elaborated into diacetate 70, this time as the TBS ether at C-25, as this protecting group was easier to remove than the acetate used in the earlier work directed toward the original stractnre (see Scheme 16.8). Stille coupling of this allylic acetate (70) then proceeded smoothly, as before, affording the complete Cj-C q backbone 71, which was successfully elaborated to the correct structure of azaspiracid-1 (1), identical in all measured physical properties ( H NMR, C NMR, Rf, [aj ) to the natural material.

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